Pharmaceutical patch for transdermal administration of (1r,4r)-6&#39;-fluoro-N,N-dimethyl-4-phenyl-4&#39;,9&#39;-dihydro-3&#39;H-spiro[cyclohexane-1,1&#39;-pyrano[3,4-b]indol]-4-amine

ABSTRACT

The invention relates to a pharmaceutical patch for transdermal administration of the pharmacologically active ingredient (1r,4r)-6′-fluro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine or a physiologically acceptable salt thereof, the patch comprising a surface layer, an adhesive layer, and a removable protective layer, wherein the adhesive layer is located between the surface layer and the removable protective layer.

The invention relates to a pharmaceutical patch for transdermal administration of the pharmacologically active ingredient (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine or a physiologically acceptable salt thereof, the patch comprising a surface layer, an adhesive layer, and a removable protective layer, wherein the adhesive layer is located between the surface layer and the removable protective layer.

The pharmacologically active ingredient according to the invention is known from the prior art to exhibit analgesic properties and is particularly suitable for the treatment of acute, visceral, neuropathic or chronic pain (cf., e.g., WO 2004/043967 and WO 2008/040481).

While the pharmacologically active ingredient according to the invention has a sufficient bioavailability so that it can be administered orally, it is desirable to provide an alternative route of systemic administration. It is known that transdermal administration of a pharmacologically active ingredient can be advantageous compared to its oral administration, e.g. with respect to patient compliance.

The working principle of a pharmaceutical patch for transdermal administration relies on the release of the pharmacologically active ingredient from the patch, its penetration into and through the skin barrier, and its entry into the systemic circulation through the perfused subcutaneous tissue, where it then develops its pharmacological effect at the targeted receptors. The penetration of a pharmacologically active ingredient through the skin is largely determined by its physicochemical properties and so far, there are only relatively few preparations of pharmacologically active ingredients that are suitable for transdermal administration.

In general, besides the desired pharmacological effect of pain relief, a pharmaceutical patch for transdermal administration of an analgesic should satisfy the following requirements:

-   -   good adhesion to the skin without skin irritations at the         contact area, even after long term application;     -   appropriate size that is as inconspicuous as possible;     -   good shelf-life and storage stability, e.g. no recrystallization         of the pharmacologically active ingredient, reduction or even         suppression of chemical degradation of the pharmacologically         active ingredient;     -   low but sufficient content of the pharmacologically active         ingredient to maintain therapeutic plasma concentrations over         extended periods of time; and     -   well adjusted flux rate to make available to the patient as much         as possible of the pharmacologically active ingredient contained         in the pharmaceutical patch over a predetermined period of time         at a constant or nearly constant flux rate.

Only a very few pharmacologically active ingredients may be administered transdermally. Typically, the transdermal administrability of a given drug can be assessed in view of some of its characteristic features (cf. T. K. Ghosh et al., Transdermal and topical drug delivery systems; Interpharm Press (Buffalo Grove, Ill., 2002)), particularly

-   -   its water solubility,     -   its melting point, and     -   its partition coefficient in the system octanol/water.

High water solubilities, low melting points as well as partition coefficients between 1 and 3.5 (log P, max. 4.0) have been reported in the literature as being generally desirable for transdermal administration.

The water solubility of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclo-hexane-1,1-pyrano[3,4-b]indol]-4-amine (free base as well as hemicitrate) is very poor (less than 0.3 μg/ml), its melting point is very high (˜300° C.) and its partition coefficient substantially outside the desirable range (log P 5.3).

Therefore, one would typically expect that this pharmacologically active ingredient cannot be administered transdermally.

It is an object of the invention to provide an advantageous pharmaceutical preparation of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine or a physiologically acceptable salt thereof.

This object has been achieved by the subject-matter of the patent claims.

It has been surprisingly found that (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine, in form of the free base or in form of its physiologically acceptable salts, can be administered transdermally, i.e. that pharmaceutical formulations can be found which release the pharmacologically active ingredient in a form that is capable of penetrating into the skin barrier and entering into the systemic circulation through the perfused subcutaneous tissue in a sufficient quantity and rate to develop its desired analgesic effect.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the accumulated permeated amount [μg/cm²] for different compositions as a function of the time [h] using a cellulose-acetate membrane.

FIG. 2 shows the accumulated permeated amount [μg/cm²] for different compositions as a function of exposure time [h] using a silicon membrane.

FIG. 3 shows the increase in pain latency (% MPE) and the plasma concentration [ng/mL] of the active ingredient as a function of the time for different compositions according to the data from example 12, study 1.

FIG. 4 shows the increase in pain latency (% MPE) and the plasma concentration [ng/mL] of the active ingredient as a function of the exposure time for different compositions according to the data from example 12, study 2.

FIG. 5 shows the plasma concentration [ng/mL] of the active ingredient as a function of the time for different compositions according to the data from example 12, study 3.

FIG. 6 shows the increase in pain latency (% MPE) of the active ingredient as a function of the time for different compositions according to the data from example 12, study 3.

FIG. 7 shows the increase in pain latency (% MPE) and the plasma concentration [ng/mL] of the active ingredient as a function of the time for different compositions according to the data from example 12, study 3.

FIG. 8 shows the AUC_(0-t) [h·ng/mL] as a function of the dose load of the patch [μg base/kg] according to example 12, study 3.

FIG. 9 shows the increase in pain latency (% MPE) and the plasma concentration [ng/mL] of the active ingredient (API free base in PEG400 or SEDDS applied in Finn chambers to approximately 3 cm²) as a function of the time for different compositions according to example 12, study 4.

FIG. 10 shows the increase in pain latency (% MPE) and the plasma concentration [ng/mL] of the active ingredient as a function of the time for different compositions according to the data from example 12, study 4 after application of Patch 12D (acrylate) and Patch 12E (silicone).

FIG. 11 shows the AUC_(0-t) [h·ng/mL] as a function of the dose load of the patch [μg base/kg] according to examples 2 and 3.

FIG. 12 shows the plasma concentration [ng/mL] of the active ingredient as a function of the time for different compositions according to example 14)

FIG. 13 shows the plasma concentration [ng/mL] of the active ingredient (API free base after application of Patch 12D, acrylate, and Patch 12E, silicone, and PEG to male minipigs) as a function of the time for different compositions according to example 14

FIG. 14 shows the plasma concentration [ng/mL] of the active ingredient (API free base after application of Patch 12D, acrylate, and Patch 12E, silicone, and PEG to female minipigs) as a function of the time for different compositions according to example 14.

FIG. 15 shows the permeation of API free base [ng] across dermatomized pig skin (incl. stratum corneum) from saturated solutions in enhancers E1 to E8 (example 24).

FIG. 16 shows the results of ex vivo testing of patches P1 to P6 across dermatomized pig skin according to the data from example 15

FIG. 17 show the results with PEG 400 as acceptor medium from example 16

FIG. 18 shows the results with ammonium acetate buffer as acceptor medium from example 16

FIG. 19 shows the EVA membrane permeation testing of polyisobutylene formulations containing API free base (19-1, 19-2, 19-3) vs. an acrylate reference patch (19-13, composition 12D) according to example 19.

FIG. 20 shows the EVA membrane permeation testing of styrenic rubber formulations containing API free base (19-4, 19-5, 19-6) vs. an acrylate reference patch (19-13, composition 12D) according to example 19.

FIG. 21 shows the EVA membrane permeation testing of silicone/PVA formulations containing API free base (18-7, 18-8, 18-9) vs. an acrylate reference patch (19-13, composition 12D) according to example 20.

FIG. 22 shows the EVA membrane permeation testing of silicone/PVP formulations containing API free base (18-19, 18-21) vs. an acrylate reference patch (19-13, composition 12D) according to example 20

FIG. 23 shows the EVA membrane permeation testing of Duro Tak® 87-2353 formulations containing API free base (21-1, 21-2, 21-3) vs. an acrylate reference patch (19-13, composition 12D) according to example 21.

FIG. 24 shows the EVA membrane permeation testing of DuroTak® 87-2051 formulations containing API free base (21-5, 21-6, 24-7) vs. an acrylate reference patch (19-13, composition 12D) according to example 21.

FIG. 25 shows the EVA membrane permeation testing of acrylate formulations containing API free base (23-1 to 23-4) vs. an acrylate reference patch (19-13, composition 12D) according to example 23.

FIG. 26 shows the EVA membrane permeation testing of Eudragit® EPO containing adhesives vs. an acrylate reference patch (19-13, composition 12D) according to example 25.

The pharmaceutical patch according to the invention comprises a surface layer, an adhesive layer, and a removable protective layer, wherein the adhesive layer is located between the surface layer and the removable protective layer.

The adhesive layer is located between the surface layer and the removable protective layer. Preferably, the surface layer forms the outer surface of the pharmaceutical patch, i.e. when the pharmaceutical patch is applied to the skin the surface layer is the visible layer of the pharmaceutical patch.

Preferably, one of the two opposing surfaces of the adhesive layer is in intimate contact with, i.e. adjacent to the removable protective layer.

In a preferred embodiment, the other of the two opposing surfaces of the adhesive layer is in intimate contact with the surface layer, which in turn preferably forms on its outer surface the outer surface of the pharmaceutical patch. According to this embodiment of the invention, the pharmaceutical patch preferably consists of surface layer, adhesive layer and removable protective layer, so that the adhesive layer contains the pharmacologically active ingredient (drug-in-adhesive).

In another preferred embodiment, the other of the two opposing surfaces of the adhesive layer is not in intimate contact with the surface layer, which in turn preferably forms on its outer surface the outer surface of the pharmaceutical patch. Thus, according to this embodiment, at least one additional layer is present between the surface layer and the adhesive layer. According to this embodiment of the invention, the pharmaceutical patch preferably comprises the surface layer, the adhesive layer, the removable protective layer and one, two, three or more additional layers between the adhesive layer and the surface layer, so that the pharmacologically active ingredient can be present in the adhesive layer and/or in any one of said additional layers.

The total thickness of the pharmaceutical patch is not particularly limited. Preferably, the total thickness of the pharmaceutical patch is within the range of from more preferably 20 to 1000 μm, still more preferably 40 to 800 μm, yet more preferably 60 to 650 μm, even more preferably 80 to 550 μm, most preferably 100 to 450 μm, and in particular 150 to 400 μm. In a preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 100±75 μm (i.e. from 25 μm to 175 μm), preferably 100±50 μm. In another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 150±100 μm, preferably 150±75 μm, more preferably 150±50 μm. In another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 200±150 μm, preferably 200±100 μm, more preferably 200±50 μm. In another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 300±250 μm, preferably 300±200 μm, more preferably 300±150 μm, still more preferably 300±100 μm, and yet more preferably 300±50 μm. In still another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 400±350 μm, preferably 400±300 μm, more preferably 400±250 μm, still more preferably 400±200 μm, yet more preferably 400±150 μm, even more preferably 400±100 μm, and most preferably 400±50 μm. In yet another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 500±400 μm, preferably 500±350 μm, more preferably 500±300 μm, still more preferably 500±250 μm, yet more preferably 500±200 μm, even more preferably 500±150 μm, most preferably 500±100 μm, and in particular 500±50 μm. In preferred embodiments, the aforementioned values include the removable protective layer. In another preferred embodiment, the aforementioned values exclude the removable protective layer.

In a preferred embodiment, the adhesive layer comprises at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.

In a preferred embodiment, the adhesive layer is adjacent to the removable protective layer and/or to the surface layer. Preferably, the adhesive layer is adjacent to the removable protective layer and to the surface layer. In a particularly preferred embodiment, the pharmaceutical patch is composed of the surface layer, the adhesive layer, and the removable protective layer and does not contain any additional layer.

In another preferred embodiment, the pharmaceutical patch further comprises at least one drug layer, which comprises at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.

Preferably, the drug layer comprises at least 10 wt.-%, more preferably at least 25 wt.-%, still more preferably at least 50 wt.-%, yet more preferably at least 75 wt.-%, even more preferably at least 85 wt.-%, most preferably at least 90 wt.-%, and in particular at least 95 wt.-% of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch. In an especially preferred embodiment, the drug layer comprises the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch. A skilled person recognizes that when the drug layer is not identical with the adhesive layer, a certain amount of the pharmacologically active ingredient migrates from the drug layer into the adjacent drug permeable layer(s) for thermodynamic reasons until an equilibrium has been reached. Thus, even if the material forming the adhesive layer did not contain any pharmacologically active ingredient when the pharmaceutical patch was manufactured, the final product typically does contain pharmacologically active ingredient not only in the drug layer but also in the adhesive layer.

In a preferred embodiment, the drug layer is located between the adhesive layer and the surface layer. The drug layer may be separated from the adhesive layer by a membrane or may be in intimate contact with, i.e. adjacent to the adhesive layer.

In a preferred embodiment, the drug layer comprises a portion of the total amount of the pharmacologically active ingredient and the adhesive layer comprises another portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.

In another preferred embodiment, the adhesive layer does not comprise any pharmacologically active ingredient upon manufacture of the pharmaceutical patch, whereas typically there is an exchange of the pharmacologically active ingredient between adjacent layers until an equilibrium between the drug permeable layers has been reached. Preferably, when the pharmaceutical patch comprises a drug layer that is separate from the adhesive layer, the drug layer is located between the adhesive layer and the surface layer, in particular adjacent to the adhesive layer. In another preferred embodiment, the drug layer and at least a part of the adhesive layer are both in contact with the same side of the removable protective layer, wherein the area of the drug layer is preferably smaller than the area of the removable protective layer. The adhesive layer may either overlap with the drug layer or be only present in that part of the removable protective layer that is not in contact with the drug layer, for example by forming a ring or a frame around the drug layer.

In a preferred embodiment, the material of the adhesive layer only covers a portion of the adjacent layer(s), e.g. assumes the form of a grid or any other suitable pattern.

The drug layer may be present in form of a liquid, a semisolid, or a solid polymer matrix.

In a preferred embodiment, the drug layer comprises a liquid containing the pharmacologically active ingredient in form of a solution or suspension.

In another preferred embodiment, the drug layer is a semisolid, such as a gel, or a solid polymer matrix wherein the pharmacologically active ingredient is dispersed.

In a preferred embodiment, the total amount of the pharmacologically active ingredient is present in molecular dispersed form.

In another preferred embodiment, only a portion of the pharmacologically active ingredient is present in molecular dispersed form, while the remainder of the pharmacologically active ingredient is present is non-molecular dispersed form (e.g. in form of droplets, crystals and the like) serving the purpose of a depot, also called “microreservoir”.

The pharmacologically active ingredient according to the invention, i.e. (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):

The pharmacologically active ingredient (free base) can alternatively be referred to as “1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole (trans)”. Unless expressly stated otherwise, all quantities refer to the weight of the free base.

The pharmacologically active ingredient can be present in the pharmaceutical patch according to the invention in form of the free base or as derivative thereof in any possible form, thereby particularly including solvates and polymorphs, salts, in particular acid addition salts and corresponding solvates and polymorphs. The hemicitrate is a preferred example of an acid addition salt.

The pharmacologically active ingredient can be present in the pharmaceutical patch according to the invention in form of the free base or in form of an acid addition salt, whereby any suitable acid capable of forming such an addition salt may be used. The conversion of the pharmacologically active ingredient into a corresponding addition salt, for example, via reaction with a suitable acid may be effected in a manner well known to those skilled in the art. Suitable acids include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. Salt formation is preferably effected in a solvent, for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solution is also suitable for the preparation of hydrochlorides.

Preferably, however, the pharmacologically active ingredient is present in form of the free base. It has been found that the transdermal bioavailability of the pharmacologically active ingredient in form of the free base is substantially higher (about 2-3 times higher) than the bioavailability of its hemicitrate.

Preferably, the pharmacologically active ingredient is contained in the adhesive layer, while a certain portion of the pharmacologically active ingredient may be contained in the adjacent layers e.g. due to migration and/or diffusion. Preferably, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 0.10 wt.-%, more preferably at least 0.20 wt.-%, still more preferably at least 0.30 wt.-%, yet more preferably at least 0.40 wt.-%, even more preferably at least 0.50 wt.-%, most preferably at least 0.60 wt.-% and in particular at least 0.70 wt.-%, relative to the total weight of the adhesive layer.

For the purpose of the specification, unless expressly stated otherwise, all weight percentages relate to the total weight of the pharmaceutical patch or to the total weight of a specific layer thereof in terms of total per dry unit. In this regard, “dry unit” shall encompass all constituents, irrespective of whether they are present in solid, semisolid or liquid form, but shall not encompass volatile solvents that are evaporated in course of the preparation of the pharmaceutical patch such as ethanol, heptane, ethyl acetate and the like. Thus, “dry unit” shall merely encompass the residual content of volatile solvent(s), if any.

In a preferred embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 1.00 wt.-%, more preferably at least 1.25 wt.-%, still more preferably at least 1.50 wt.-%, yet more preferably at least 1.75 wt.-%, even more preferably at least 2.00 wt.-%, most preferably at least 2.25 wt.-% and in particular at least 2.50 wt.-%, relative to the total weight of the adhesive layer. In another preferred embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 2.75 wt.-%, more preferably at least 3.00 wt.-%, still more preferably at least 3.25 wt.-%, yet more preferably at least 3.50 wt.-%, even more preferably at least 3.75 wt.-%, most preferably at least 4.00 wt.-% and in particular at least 4.25 wt.-%, relative to the total weight of the adhesive layer. In still another preferred embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 4.50 wt.-%, more preferably at least 4.75 wt.-%, still more preferably at least 5.00 wt.-%, yet more preferably at least 5.25 wt.-%, even more preferably at least 5.50 wt.-%, most preferably at least 5.75 wt.-% and in particular at least 6.00 wt.-%, relative to the total weight of the adhesive layer.

It is principally desirable to provide the pharmacologically active ingredient in the adhesive layer at comparatively high concentrations, as this may positively influence the flux rate. As there is evidence, however, that the pharmacologically active ingredient tends to recrystallize at high concentrations, the concentration of the pharmacologically active ingredient in the adhesive layer is preferably at most 7.50 wt.-%, more preferably at most 5.00 wt.-%, still more preferably at most 2.50 wt.-%, yet more preferably at most 2.00 wt.-%, even more preferably at most 1.50 wt.-%, most preferably at most 1.00 wt.-%, and in particular at most 0.80 wt.-%, relative to the total weight of the adhesive layer (total per dry unit).

The total dose of the pharmacologically active ingredient that is contained in the pharmaceutical patch is not particularly limited and may depend upon various factors such as body weight of the subject to be treated and duration of application on the skin. The pharmacologically active ingredient is contained in the pharmaceutical patch in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the form of the pharmacologically active ingredient being present, the condition being treated, the severity of said condition, the patient being treated, and the prescribed duration of application of the pharmaceutical patch to the skin.

In a preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 20±15 μg (i.e. from 5 μg to 35 μg), more preferably 20±12.5 μg, still more preferably 20±10 μg, most preferably 20±7.5 μg, and in particular 20±5 μg is systemically administered per day.

In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 40±35 μg, more preferably 40±30 μg, still more preferably 40±25 μg, yet more preferably 40±20 μg, even more preferably 40±15 μg, most preferably 40±10 μg, and in particular 40±5 μg is systemically administered per day.

In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 60±45 μg, more preferably 60±35 μg, still more preferably 60±25 μg, yet more preferably 60±20 μg, even more preferably 60±15 μg, most preferably 60±10 μg, and in particular 60±5 μg is systemically administered per day.

In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 80±70 μg, more preferably 80±60 μg, still more preferably 80±50 μg, yet more preferably 80±40 μg, even more preferably 80±30 μg, most preferably 80±20 μg, and in particular 80±10 μg is systemically administered per day.

In still another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 160±140 μg, more preferably 160±120 μg, still more preferably 160±100 μg, yet more preferably 160±80 μg, even more preferably 160±60 μg, most preferably 160±40 μg, and in particular 160±20 μg is systemically administered per day.

In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 280±250 μg, more preferably 280±200 μg, still more preferably 280±150 μg, yet more preferably 280±100 μg, even more preferably 280±75 μg, most preferably 280±50 μg, and in particular 280±25 μg is systemically administered per day.

In yet another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 400±350 μg, more preferably 400±300 μg, still more preferably 400±250 μg, yet more preferably 400±200 μg, even more preferably 400±150 μg, most preferably 400±100 μg, and in particular 400±50 μg is systemically administered per day.

In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 600±400 μg, more preferably 600±300 μg, still more preferably 600±200 μg, yet more preferably 600±150 μg, even more preferably 600±100 μg, most preferably 600±75 μg, and in particular 600±50 μg is systemically administered per day.

Preferably, the total dose of the pharmacologically active ingredient that is contained in the pharmaceutical patch satisfies the following requirement:

${{dose}\mspace{14mu} {contained}\mspace{14mu} {in}\mspace{14mu} {{patch}\mspace{14mu}\lbrack{\mu g}\rbrack}} = {\frac{\begin{matrix} {{intended}\mspace{14mu} {duration}\mspace{14mu} {of}\mspace{14mu} {{{application}\mspace{14mu}\lbrack{days}\rbrack} \cdot}} \\ {{desired}\mspace{14mu} {systemic}\mspace{14mu} {daily}\mspace{14mu} {{dose}\mspace{14mu}\lbrack{\mu g}\rbrack}} \end{matrix}}{{bioavailability}\mspace{14mu}\lbrack\%\rbrack} \cdot 100}$

In a preferred embodiment, the desired daily dose amounts to 20±15 μg (i.e. from 5 μg to 35 μg), more preferably 20±10 μg; or 40±20 μg, more preferably 40±10 μg; or 80±40 μg, more preferably 80±20 μg; or 160±80 μg, more preferably 160±40 μg; or 400±200 μg, more preferably 400±100 μg. The intended duration of application is preferably 1, 2, 3, 4, 5, 6, or 7 days. The bioavailability is preferably as high as possible and can be determined for a given pharmaceutical patch by routine experimentation.

Preferably, the transdermal bioavailability is within the range of 2.0±1.8% (i.e. from 0.2% to 3.8%), more preferably 2.0±1.6%, still more preferably 2.0±1.4%, yet more preferably 2.0±1.2%, even more preferably 2.0±1.0%, most preferably 2.0±0.8%, and in particular 2.0±0.6%. In a preferred embodiment, the transdermal bioavailability is within the range of 5.0±4.5%, more preferably 5.0±4.0%, still more preferably 5.0±3.5%, yet more preferably 5.0±3.0%, even more preferably 5.0±2.5%, most preferably 5.0±2.0%, and in particular 5.0±1.5%. In another preferred embodiment, the transdermal bioavailability is within the range of 10±8.0%, more preferably 10±7.0%, still more preferably 10±6.0%, yet more preferably 10±5.0%, even more preferably 10±4.0%, most preferably 10±3.0%, and in particular 10±2.0%. In still another preferred embodiment, the transdermal bioavailability is within the range of 15±13%, more preferably 15±11%, still more preferably 15±9.0%, yet more preferably 15±7.0%, even more preferably 15±6.0%, most preferably 15±5.0%, and in particular 15±4.0%. In yet another preferred embodiment, the transdermal bioavailability is within the range of 20±18%, more preferably 20±16%, still more preferably 20±14%, yet more preferably 20±12%, even more preferably 20±10%, most preferably 20±8.0%, and in particular 20±6.0%.

Preferably, the area concentration of the pharmacologically active ingredient in the adhesive layer and the drug layer, respectively, is within the range of from 0.01 to 10 g/m².

In a preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 0.20±0.18 g/m² (i.e. from 0.02 g/m² to 0.38 g/m²), more preferably 0.20±0.15 g/m², still more preferably 0.20±0.13 g/m², yet more preferably 0.20±0.10 g/m², even more preferably 0.20±0.08 g/m², most preferably 0.20±0.05 g/m², and in particular 0.20±0.03 g/m².

In another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 0.40±0.35 g/m², more preferably 0.40±0.30 g/m², still more preferably 0.40±0.25 g/m², yet more preferably 0.40±0.20 g/m², even more preferably 0.40±0.15 g/m², most preferably 0.40±0.10 g/m², and in particular 0.40±0.05 g/m². In still another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 1.00±0.85 g/m², more preferably 1.00±0.80 g/m², still more preferably 1.00±0.75 g/m², yet more preferably 1.00±0.70 g/m², even more preferably 1.00±0.65 g/m², most preferably 1.00±0.60 g/m², and in particular 1.00±0.55 g/m². In yet another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 3.00±2.50 g/m², more preferably 3.00±2.25 g/m², still more preferably 3.00±2.00 g/m², yet more preferably 3.00±1.75 g/m², even more preferably 3.00±1.50 g/m², most preferably 3.00±1.25 g/m², and in particular 3.00±1.00 g/m². In another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 6.00±5.00 g/m², more preferably 6.00±4.50 g/m², still more preferably 6.00±4.00 g/m², yet more preferably 6.00±3.50 g/m², even more preferably 6.00±3.00 g/m², most preferably 6.00±2.50 g/m², and in particular 6.00±2.00 g/m².

In a preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of at least 1.0 ng·cm⁻²·h⁻¹ or at least 2.5 ng·cm⁻²·h⁻¹ or at least 5.0 ng·cm⁻²·h⁻¹; still more preferably at least 7.5 ng·ng·h⁻¹ or at least 10 ng·cm⁻² 2·h⁻¹ or at least 15 ng·cm⁻²·h⁻¹; still more preferably at least 25 ng·cm⁻²·h⁻¹ or at least 50 ng·cm⁻²·h⁻¹ or at least 75 ng·cm⁻²·h⁻¹; yet more preferably at least 100 ng·cm⁻²·h⁻¹ or at least 150 ng·cm⁻²·h⁻¹ or at least 200 ng·cm⁻²·h⁻¹; even more preferably at least 250 ng·cm⁻²·h⁻¹ or at least 300 ng·cm⁻²·h⁻¹ or at least 350 ng·cm⁻²·h⁻¹; most preferably at least 400 ng·cm⁻²·h⁻¹ or at least 450 ng·cm⁻²·h⁻¹ or at least 500 ng·h⁻¹; and in particular at least 550 ng·cm⁻²·h⁻¹ or at least 600 ng·cm⁻²·h⁻¹ or at least 650 ng·cm⁻²·h⁻¹.

In a preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 5.0±4.6 ng·cm⁻²·h⁻¹ (i.e. from 0.4 ng·cm⁻²·h⁻¹ to 9.6 ng·cm⁻²·h⁻¹), more preferably 5.0±4.2 ng·cm⁻²·h⁻¹, still more preferably 5.0±3.8 ng·cm⁻²·h⁻¹, yet more preferably 5.0±3.4 ng·cm⁻²·h⁻¹, even more preferably 5.0±3.0 ng·cm⁻²·h⁻¹, most preferably 5.0±2.6 ng·cm⁻²·h⁻¹ and oin particular 5.0±2.2 ng·cm⁻²·h⁻¹.

In another preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 50±46 ng·cm⁻²·h⁻¹, more preferably 50±42 ng·cm⁻²·h⁻¹, still more preferably 50±38 ng·cm⁻²·h⁻¹, yet more preferably 50±34 ng·cm⁻²·h⁻¹, even more preferably 50±30 ng·cm⁻²·h⁻¹, most preferably 50±26 ng·cm⁻²·h⁻¹ and in particular 50±22 ng·cm⁻²·h⁻¹.

In still another preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 500±460 ng·cm⁻²·h⁻¹, more preferably 500±420 ng·cm⁻²·h⁻¹, still more preferably 500±380 ng·cm⁻²·h⁻¹, yet more preferably 500±340 ng·cm⁻²·h⁻¹, even more preferably 500±300 ng·cm⁻²·h⁻¹, most preferably 500±260 ng·cm⁻²·h⁻¹ and in particular 500±220 ng·cm⁻²·h⁻¹.

In yet another preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 5000±4600 ng·cm⁻²·h⁻¹, more preferably 5000±4200 ng·cm⁻²·h⁻¹, still more preferably 5000±3800 ng·cm⁻²·h⁻¹, yet more preferably 5000±3400 ng·cm⁻²·h⁻¹, even more preferably 5000±3000 ng·cm⁻²·h⁻¹, most preferably 5000±2600 ng·cm⁻²·h⁻¹ and in particular 5000±2200

In a preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of at least 10 pg·ml⁻¹, at least 25 pg·ml⁻¹ or at least 50 pg·ml⁻¹; more preferably at least 75 pg·ml⁻¹, at least 100 pg·ml⁻¹ or at least 150 pg·ml⁻¹; still more preferably at least 200 pg·ml⁻¹, at least 250 pg·ml⁻¹ or at least 300 pg·ml⁻¹; yet more preferably at least 350 pg·ml⁻¹, at least 400 pg·ml⁻¹ or at least 450 pg·ml⁻¹; even more preferably at least 500 pg·ml⁻¹, at least 550 pg·ml⁻¹ or at least 600 pg·ml⁻¹; most preferably at least 650 pg·ml⁻¹, at least 700 pg·ml⁻¹ or at least 750 pg·ml⁻¹; and in particular at least 800 pg·ml⁻¹, at least 850 pg·ml⁻¹ or at least 900 pg·ml⁻¹.

In a preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 10±8.0 pg·ml⁻¹, more preferably 10±7.0 pg·ml⁻¹, still more preferably 10±6.0 pg·ml⁻¹, yet more preferably 10±5.0 pg·ml⁻¹, even more preferably 10±4.0 pg·ml⁻¹, most preferably 10±3.0 pg·ml⁻¹, and in particular 10±2.0 pg·ml⁻¹.

In another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 20±16 pg·ml⁻¹, more preferably 20±14 pg·ml⁻¹, still more preferably 20±12 pg−ml⁻¹, yet more preferably 20±10 pg−ml⁻¹, even more preferably 20±8.0 pg−ml⁻¹, most preferably 20±6.0 pg·ml⁻¹, and in particular 20±4.0 pg·ml⁻¹.

In still another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 40±32 pg·ml⁻¹, more preferably 40±28 pg·ml⁻¹, still more preferably 40±24 pg·ml⁻¹, yet more preferably 40±20 pg·ml⁻¹, even more preferably 40±16 pg·ml⁻¹, most preferably 40±12 pg·ml⁻¹, and in particular 40±8.0 pg·ml⁻¹.

In yet another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 75±64 pg·ml⁻¹, more preferably 75±56 pg·ml⁻¹, still more preferably 75±48 pg·ml⁻¹, yet more preferably 75±40 pg·ml⁻¹, even more preferably 75±32 pg·ml⁻¹, most preferably 75±24 pg·ml⁻¹, and in particular 75±16 pg·ml⁻¹.

In another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 150±128 pg·ml⁻¹, more preferably 150±112 pg·ml⁻¹, still more preferably 150±96 pg·ml⁻¹, yet more preferably 150±80 pg·ml⁻¹, even more preferably 150±64 pg·ml⁻¹, most preferably 150±48 pg·ml⁻¹, and in particular 150±32 pg·ml⁻¹.

In still another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 300±256 pg·ml⁻¹, more preferably 300±224 pg·ml⁻¹, still more preferably 300±192 pg·ml⁻¹, yet more preferably 300±160 pg·ml⁻¹, even more preferably 300±128 pg·ml⁻¹, most preferably 300±96 pg·ml⁻¹, and in particular 300±64 pg·ml⁻¹.

In yet another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 600±512 pg·ml⁻¹, more preferably 600±448 pg·ml⁻¹, still more preferably 600±384 pg·ml⁻¹, yet more preferably 600±320 pg·ml⁻¹, even more preferably 600±256 pg·ml⁻¹, most preferably 600±192 pg·ml⁻¹, and in particular 600±128 pg·ml⁻¹.

In another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of at least 1.0 ng·ml⁻¹, at least 2.5 ng·ml⁻¹ or at least 5.0 ng·ml⁻¹; more preferably at least 7.5 ng·ml⁻¹, at least 10.0 ng·ml⁻¹ or at least 15.0 ng·ml⁻¹; still more preferably at least 20.0 ng·ml⁻¹, at least 25.0 ng·ml⁻¹ or at least 30.0 ng·ml⁻¹; yet more preferably at least 35.0 ng·ml⁻¹, at least 40.0 ng·ml⁻¹ or at least 45.0 ng·ml⁻¹; even more preferably at least 50.0 ng·ml⁻¹, at least 55.0 ng·ml⁻¹ or at least 60.0 ng·ml⁻¹; most preferably at least 65.0 ng·ml⁻¹, at least 70.0 ng·ml⁻¹ or at least 75.0 ng·ml⁻¹; and in particular at least 80.0 ng·ml⁻¹, at least 85.0 ng·ml⁻¹ or at least 90.0 ng·ml⁻¹.

The pharmaceutical patch according to the invention preferably contains a crystallization inhibitor which inhibits the crystallization of the pharmacologically active ingredient within the adhesive layer and drug layer, respectively. Thus, the crystallization inhibitor is preferably contained in the same layer as the pharmacologically active ingredient. Preferably, the content of the crystallization inhibitor within said layer is within the range of from 1.0 to 20 wt.-%, more preferably 2.5 to 17.5 wt.-%, still more preferably 5.0 to 15 wt.-%, yet more preferably 6.0 to 14 wt.-%, even more preferably 7.0 to 13 wt.-%, most preferably 8.0 to 12 wt.-%, and in particular 9.0 to 11 wt.-%, relative to the total weight of said layer. Preferred crystallization inhibitors include but are not limited to polyvinylpyrrolidones (povidone, polyvidone) (e.g. Kollidon 25), N-vinyl-1-aza-cycloheptan-2-one homopolymers, N-vinylpiperidin-2-one homopolymers, polyethylene glycol, poloxamer (e.g. Lutrol F127), and copovidone (e.g. Kollidon VA64).

Preferably, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of from 1000:1 to 1:1000, more preferably 250:1 to 1:250, still more preferably 100:1 to 1:100, yet more preferably 50:1 to 1:50, even more preferably 25:1 to 1:25, most preferably 10:1 to 1:10, and in particular 5:1 to 1:5.

In a preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:10±7 (i.e. from 1:3 to 1:17), more preferably 1:10±6, still more preferably 1:10±5, yet more preferably 1:10±4, even more preferably 1:10±3, most preferably 1:10±2, and in particular 1:10±1. In a preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:20±14, more preferably 1:20±12, still more preferably 1:20±10, yet more preferably 1:20±8, even more preferably 1:20±6, most preferably 1:20±4, and in particular 1:20±2. In another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:45±37, more preferably 1:45±35, still more preferably 1:45±33, yet more preferably 1:45±31, even more preferably 1:45±29, most preferably 1:45±27, and in particular 1:45±25. In still another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:70±42, more preferably 1:70±36, still more preferably 1:70±30, yet more preferably 1:70±24, even more preferably 1:70±18, most preferably 1:70±12, and in particular 1:70±6. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:90±70, more preferably 1:90±60, still more preferably 1:90±50, yet more preferably 1:90±40, even more preferably 1:90±30, most preferably 1:90±20, and in particular 1:90±10. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:110±70, more preferably 1:110±60, still more preferably 1:110±50, yet more preferably 1:110±40, even more preferably 1:110±30, most preferably 1:110±20, and in particular 1:110±10.

The pharmaceutical patch according to the invention preferably contains a permeation component which enhances percutaneous penetration and permeation of the pharmacologically active ingredient through human skin, i.e. one or more percutaneous penetration enhancers. Percutaneous penetration enhancers are known to the skilled person (cf., e.g., Smith et al., Percutaneous Penetration Enhancers, CRC Press, 1995).

Preferably, the layer of the pharmaceutical patch which contains the pharmacologically active ingredient, i.e. the adhesive layer and/or the drug layer, contains at least one percutaneous penetration enhancer.

Preferably, the relative weight ratio of the pharmacologically active ingredient to the permeation component is within the range of from 25:1 to 1:1000, more preferably 10:1 to 1:250, still more preferably 5:1 to 1:100, yet more preferably 1:1 to 1:50, even more preferably 1:2 to 1:25, most preferably 1:6 to 1:20, and in particular 1:9 to 1:17.

Preferably, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of from 1000:1 to 1:1000, more preferably 250:1 to 1:250, still more preferably 100:1 to 1:100, yet more preferably 50:1 to 1:50, even more preferably 25:1 to 1:25, most preferably 10:1 to 1:10, and in particular 5:1 to 1:5.

In a preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:20±14 (i.e. from 1:6 to 1:34), more preferably 1:20±12, still more preferably 1:20±10, yet more preferably 1:20±8, even more preferably 1:20±6, most preferably 1:20±4, and in particular 1:20±2. In another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:45±37, more preferably 1:45±35, still more preferably 1:45±33, yet more preferably 1:45±31, even more preferably 1:45±29, most preferably 1:45±27, and in particular 1:45±25. In still another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:70±42, more preferably 1:70±36, still more preferably 1:70±30, yet more preferably 1:70±24, even more preferably 1:70±18, most preferably 1:70±12, and in particular 1:70±6. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:90±70, more preferably 1:90±60, still more preferably 1:90±50, yet more preferably 1:90±40, even more preferably 1:90±30, most preferably 1:90±20, and in particular 1:90±10. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:110±70, more preferably 1:110±60, still more preferably 1:110±50, yet more preferably 1:110±40, even more preferably 1:110±30, most preferably 1:110±20, and in particular 1:110±10.

Preferably, the permeation component is contained in the same layer of the pharmaceutical patch that also contains the pharmacologically active ingredient or at least a portion thereof. Preferably, the content of the permeation component within said layer is within the range of from 1.0 to 20 wt.-%, more preferably 2.5 to 17.5 wt.-%, still more preferably 5.0 to 15 wt.-%, yet more preferably 6.0 to 14 wt.-%, even more preferably 7.0 to 13 wt.-%, most preferably 8.0 to 12 wt.-%, and in particular 9.0 to 11 wt.-%, relative to the total weight of said layer.

In a preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 4.0±3.5 (i.e. from 0.5 to 7.5), more preferably 4.0±3.0, still more preferably 4.0±2.5, yet more preferably 4.0±2.0, even more preferably 4.0±1.5, most preferably 4.0±1.0, and in particular 4.0±0.5. In another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 8±7, more preferably 8±6, still more preferably 8±5, yet more preferably 8±4, even more preferably 8±3, most preferably 8±2, and in particular 8±1. In still another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 12±7, more preferably 12±6, still more preferably 12±5, yet more preferably 12±4, even more preferably 12±3, most preferably 12±2, and in particular 12±1. In yet another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 16±7, more preferably 16±6, still more preferably 16±5, yet more preferably 16±4, even more preferably 16±3, most preferably 16±2, and in particular 16±1. In another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 20±7, more preferably 20±6, still more preferably 20±5, yet more preferably 20±4, even more preferably 20±3, most preferably 20±2, and in particular 20±1. In another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 24±7, more preferably 24±6, still more preferably 24±5, yet more preferably 24±4, even more preferably 24±3, most preferably 24±2, and in particular 24±1.

Preferred percutaneous penetration enhancers include but are not limited to:

-   -   a) sulfoxides such as dimethylsulfoxide (DMSO) and         decylmethylsulfoxide;     -   b) ethers such as diethylene glycol monoethyl ether (transcutol)         and diethylene glycol monomethyl ether;     -   c) surfactants such as sodium laurate, sodium lauryl sulfate,         cetyltrimethylammonium bromide, benzalkonium chloride,         poloxamers, polysorbates (e.g. polysorbate 80) and lecithin;     -   d) 1-substituted azacycloheptan-2-ones such as         1-n-dodecylcyclazacycloheptan-2-one;     -   e) alcohols and fatty alcohols such as ethanol, propanol,         octanol, dodecanol, oleyl alcohol, benzyl alcohol, and the like;     -   f) polyols, esters of polyols and ethers of polyols such as         propylene glycol, ethylene glycol, diethylene glycol,         dipropylene glycol, glycerol, butanediol, polyethylene glycol,         polyvinyl alcohol (e.g. Mowiol 4-88), triacetine and         polyethylene glycol monolaurate;     -   g) organic acids such as salicylic acid and salicylates, citric         acid, levulinic acid, caprylic acid and succinic acid; as well         as dicarboxylic acids and their esters such as dibutylene         sebacate;     -   h) fatty acids such as lauric acid, oleic acid and valeric acid;         fatty acid esters such as isopropyl myristate, isopropyl         palmitate, methylpropionate, propylene glycol monolaureate,         lauryl lactate, oleyl oleate and ethyl oleate;     -   i) amides and other nitrogenous compounds such as urea,         dimethylacetamide, dimethylformamide, 2-pyrrolidone,         1-methyl-2-pyrrolidone, ethanolamine, diethanolamine,         triethanolamine and laurocapram (Azone®);     -   j) terpenes;     -   k) alkanones;     -   l) other oligomers or polymers;         and mixtures of any of the foregoing.

Preferably, the permeation component comprises as percutaneous penetration enhancer a non-cyclic compound of formula C_(2n)H_(4n+2)O_(n), where index n is 2, 3 or 4; preferably diethylene glycol monomethylether, dipropylene glycol or a mixture thereof.

Preferably, the permeation component comprises one or more percutaneous penetration enhancers selected from transcutol (diethylene glycol monoethylether), oleyl alcohol, dipropylene glycol, levulinic acid and mixtures thereof.

Preferably, the pharmaceutical patch has an area of at least 5 cm², more preferably at least 7.5 cm², still more preferably at least 10 cm², and most preferably at least 15 cm².

In a preferred embodiment, the pharmaceutical patch has an area, i.e. total surface area when being applied to the skin, within the range of 200±150 cm² (i.e. from 50 cm² to 350 cm²), more preferably 200±125 cm², still more preferably 200±100 cm², yet more preferably 200±75 cm², even more preferably 150±50 cm², most preferably 150±25 cm², and in particular 150±10 cm². In another preferred embodiment, the pharmaceutical patch has an area within the range of 300±150 cm², more preferably 300±125 cm², still more preferably 300±100 cm², yet more preferably 300±75 cm², even more preferably 300±50 cm², most preferably 300±25 cm², and in particular 300±10 cm². In still another preferred embodiment, the pharmaceutical patch has an area within the range of 400±150 cm², more preferably 400±125 cm², still more preferably 400±100 cm², yet more preferably 400±75 cm², even more preferably 400±50 cm², most preferably 400±25 cm², and in particular 400±10 cm².

In a preferred embodiment, the pharmaceutical patch has an area, i.e. total surface area when being applied to the skin, within the range of 25±20 cm², more preferably 25±15 cm², still more preferably 25±10 cm². In another preferred embodiment, the pharmaceutical patch has an area, i.e. total surface area when being applied to the skin, within the range of 50±40 cm², more preferably 50±35 cm², still more preferably 50±30 cm², yet more preferably 50±25 cm², even more preferably 50±20 cm², most preferably 50±15 cm², and in particular 50±10 cm². In still another preferred embodiment, the pharmaceutical patch has an area within the range of 75±40 cm², more preferably 75±35 cm², still more preferably 75±30 cm², yet more preferably 75±25 cm², even more preferably 75±20 cm², most preferably 75±15 cm², and in particular 75±10 cm². In yet another preferred embodiment, the pharmaceutical patch has an area within the range of 100±80 cm², more preferably 100±60 cm², still more preferably 100±50 cm², yet more preferably 100±40 cm², even more preferably 100±30 cm², most preferably 100±20 cm², and in particular 100±10 cm². In another preferred embodiment, the pharmaceutical patch has an area within the range of 150±80 cm², more preferably 150±60 cm², still more preferably 150±50 cm², yet more preferably 150±40 cm², even more preferably 150±30 cm², most preferably 150±20 cm², and in particular 150±10 cm². In another preferred embodiment, the pharmaceutical patch has an area within the range of 200±80 cm², more preferably 200±60 cm², still more preferably 200±50 cm², yet more preferably 200±40 cm², even more preferably 200±30 cm², most preferably 200±20 cm², and in particular 200±10 cm². In another preferred embodiment, the pharmaceutical patch has an area within the range of 250±80 cm², more preferably 250±60 cm², still more preferably 250±50 cm², yet more preferably 250±40 cm², even more preferably 250±30 cm², most preferably 250±20 cm², and in particular 250±10 cm².

The pharmaceutical patch according to the invention comprises a surface layer.

The term “surface layer” as used herein refers to any layer that represents the surface layer after the application of the pharmaceutical patch. This definition includes permanent backing layer commonly used for pharmaceutical patches as well as thin non-removable films that are typically used in thin flexible patches.

In a preferred embodiment, the surface layer comprises one or more polymers selected from the group consisting of polyurethanes, polyester elastomers, polyether block amides, polyacrylates, ethylene vinyl acetates, ethylene acrylate copolymers, ionomer resins, polyvinyl chloride, polyvinylidene chloride, polyesters and polyolefins, such as polyethylene; polyolefins, in particular polyethylene, polyesters, ethylene vinylacetate copolymers and polyurethanes are particularly preferred.

The surface layer may be a laminate, preferably comprising a polymer film, such as a polyester film, and aluminum foil and/or heat seal layer.

In a preferred embodiment, the surface layer consists of a polyester film and an ethylene vinylacetate copolymer heat seal layer.

The thickness of the surface layer is not particularly limited. Preferably, the surface layer has a thickness within the range of from 0.1 to 5000 μm. In a preferred embodiment, the surface layer has a thickness within the range of from 0.5 to 1000 μm, more preferably from 1 to 750 μm, still more preferably from 5 to 500 μm, most preferably from 10 to 250 μm, and in particular from 20 to 150 μm or from 40 to 100 μm.

In a preferred embodiment, the surface layer has a thickness within the range of 25±20 μm (i.e. from 5 μm to 45 μm), more preferably 25±15 μm, still more preferably 25±10 μm, and yet more preferably 25±5 μm.

The pharmaceutical patch according to the invention comprises a removable protective layer (release liner).

Preferably, the removable protective layer comprises a polymer film and a silicone coating or fluoropolymer coating. Preferably, the polymer film is a polyolefin, in particular polyethylene or polypropylene film or polyester, in particular polyethylene terephthalate film.

In a preferred embodiment, the removable protective layer is a silicone coated polyolefin or silicone coated polyester film, such as a silicone coated polyethylene terephthalate, polypropylene or polyethylene film.

In another preferred embodiment, the removable protective layer is a fluoropolymer coated polyolefin or polyester film, such as a fluoropolymer coated polyethylene terephthalate, polypropylene or polyethylene film.

The thickness of the removable protective layer is not particularly limited. Preferably, the removable protective layer has a thickness within the range of from 0.1 to 500 μm. In a preferred embodiment, the removable protective layer has a thickness within the range of from 0.5 to 400 μm, more preferably from 1 to 300 μm, still more preferably from 5 to 250 μm, most preferably from 10 to 200 μm, and in particular from 20 to 150 μm or from 40 to 100 μm.

In a preferred embodiment, the removable protective layer has a thickness within the range of 75±70 μm (i.e. from 5 μm to 145 μm), more preferably 75±60 μm, still more preferably 75±50 μm, yet more preferably 75±40 μm, even more preferably 75±30 μm, most preferably 75±20 μm, and in particular 75±10 μm. In another preferred embodiment, the removable protective layer has a thickness within the range of 100±70 μm, more preferably 100±60 μm, still more preferably 100±50 μm, yet more preferably 100±40 μm, even more preferably 100±30 μm, most preferably 100±20 μm, and in particular 100±10 μm.

The pharmaceutical patch according to the invention comprises an adhesive layer.

In a preferred embodiment, the adhesive layer comprises at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch. Preferably, the adhesive layer comprises at least 10 wt.-%, more preferably at least 25 wt.-%, still more preferably at least 50 wt.-%, yet more preferably at least 75 wt.-%, most preferably at least 90 wt.-%, and in particular at least 95 wt.-% of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.

In another preferred embodiment, the adhesive layer does not contain the pharmacologically active ingredient. According to this embodiment, the pharmaceutical patch comprises an additional drug layer that in turn contains the total amount or at least a portion of the pharmacologically active ingredient, taking into account that after manufacture there typically is an exchange of the pharmacologically active ingredient between adjacent layers until an equilibrium has been reached.

Preferably, the adhesive layer comprises a polymer that forms a matrix in which the pharmacologically active ingredient is dispersed (drug-in-adhesive).

Preferably, the adhesive layer comprises a pressure sensitive adhesive selected from the group consisting of polysilicone based pressure sensitive adhesives, polyacrylate based pressure sensitive adhesives, polyisobutylene based pressure sensitive adhesives, and styrenic rubber based pressure sensitive adhesives.

The thickness of the adhesive layer is not particularly limited and may depend upon a number of factors such as function within the patch (e.g. drug-in-adhesive), content of pharmacologically active ingredient and excipients, prescribed duration of application of pharmaceutical patch on the skin, and the like.

Preferably, the adhesive layer has a thickness within the range of from 1.0 to 1000 μm.

In a preferred embodiment, the adhesive layer has a thickness within the range of from 50±35 μm (i.e. from 15 μm to 85 μm), more preferably 50±30 μm, still more preferably 50±25 μm, yet more preferably 50±20 μm, even more preferably 50±15 μm, most preferably 50±10 μm, and in particular 50±5 μm. In another preferred embodiment, the adhesive layer has a thickness within the range of from 75±70 μm, more preferably 75±60 μm, still more preferably 75±50 μm, yet more preferably 75±40 μm, even more preferably 75±30 μm, most preferably 75±20 μm, and in particular 75±10 μm. In still another preferred embodiment, the adhesive layer has a thickness within the range of from 100±70 μm, more preferably 100±60 μm, still more preferably 100±50 μm, yet more preferably 100±40 μm, even more preferably 100±30 μm, most preferably 100±20 μm, and in particular 100±10 μm. In yet another preferred embodiment, the adhesive layer has a thickness within the range of from 200±175 μm, more preferably 200±150 μm, still more preferably 200±125 μm, yet more preferably 200±100 μm, even more preferably 200±75 μm, most preferably 200±50 μm, and in particular 200±25 μm. In another preferred embodiment, the adhesive layer has a thickness within the range of from 300±175 μm, more preferably 300±150 μm, still more preferably 300±125 μm, yet more preferably 300±100 μm, even more preferably 300±75 μm, most preferably 300±50 μm, and in particular 300±25 μm. In still another preferred embodiment, the adhesive layer has a thickness within the range of from 400±175 μm, more preferably 400±150 μm, still more preferably 400±125 μm, yet more preferably 400±100 μm, even more preferably 400±75 μm, most preferably 400±50 μm, and in particular 400±25 μm. In yet another preferred embodiment, the adhesive layer has a thickness within the range of from 500±175 μm, more preferably 500±150 μm, still more preferably 500±125 μm, yet more preferably 500±100 μm, even more preferably 500±75 μm, most preferably 500±50 μm, and in particular 500±25 μm.

Preferably, particularly when the adhesive layer contains the pharmacologically active ingredient or a portion thereof, the area weight of the adhesive layer is within the range of from 1.0 to 160 g/m², more preferably 5.0 to 125 g/m² or 45 to 155 g/m², still more preferably 10 to 100 g/m² or 55 to 145 g/m², yet more preferably 20 to 90 g/m² or 65 to 135 g/m², even more preferably 30 to 80 g/m² or 75 to 125 g/m², most preferably 40 to 70 g/m² or 85 to 115 g/m², and in particular 50 to 60 g/m² or 95 to 105 g/m².

In preferred embodiments a comparatively low area weight may positively influence the shelf-life of the pharmaceutical patch.

The ratio of the thickness of the surface layer to the thickness of the adhesive layer is not particularly limited. In a preferred embodiment, the thickness of the surface layer is greater than the thickness of the adhesive layer. In another preferred embodiment, the thickness of the adhesive layer is greater than the thickness of the surface layer.

In a preferred embodiment, the adhesive layer provides a peel strength of 5.5±5.0 N/25 mm, more preferably 5.5±4.5 N/25 mm, still more preferably 5.5±4.0 N/25 mm, yet more preferably 5.5±3.5 N/25 mm, even more preferably 5.5±3.0 N/25 mm, most preferably 5.5±2.5 N/25 mm, and in particular 5.5±2.0 N/25 mm.

In another preferred embodiment, the adhesive layer provides a peel strength of 2.0±1.8 N/25 mm, more preferably 2.0±1.6 N/25 mm, still more preferably 2.0±1.4 N/25 mm, yet more preferably 2.0±1.2 N/25 mm, even more preferably 2.0±1.0 N/25 mm, most preferably 2.0±0.8 N/25 mm, and in particular 2.0±0.6 N/25 mm.

Preferably, the peel test is performed as further specified in the experimental section.

In a preferred embodiment, the pressure sensitive adhesive is a polysilicone based pressure sensitive adhesive. Preferably, said polysilicone based pressure sensitive adhesive forms a matrix in which the pharmacologically active ingredient is embedded. Polysilicone based pressure sensitive adhesives are commercially available, e.g. under the trademarks BIO-PSA 7-4301, BIO-PSA 7-4302, BIO-PSA 7-4302/3, BIO-PSA 7-4201, BIO-PSA 7-4202, BIO-PSA 7-4101, BIO-PSA 7-4102, BIO-PSA 7-4601, BIO-PSA 7-4602, BIO-PSA 7-4602/3, BIO-PSA 7-4501, BIO-PSA 7-4502, BIO-PSA 7-4503, BIO-PSA 7-4401 and BIO-PSA 7-4402 by Dow Corning Corporation. The polysilicone based pressure sensitive adhesive preferably contains a solvent such as ethyl acetate or heptane and has a solids content of approx. 55-65 wt.-% solids before being dried during the preparation of the plaster. Especially preferred polysilicone based adhesives are commercially available by Dow Corning Corporation under the trademarks BIO PSA 7-4501 (solvent: heptane); BIO PSA 7-4502 (solvent: ethyl acetate); and BIO PSA 7-4503 (solvent: toluene).

In a preferred embodiment, the pressure sensitive adhesive is a polysilicone based pressure sensitive adhesive that is supplied in heptane or ethyl acetate. These solvents are typically removed during the manufacture of the pharmaceutical patch, though residual traces of solvent may be analytically detectable.

Preferably, the silicone polymers contained in the polysilicone based pressure sensitive adhesives are produced through a condensation reaction of a silanol endblocked polydimethylsiloxane (PDMS) with a silicate resin.

Preferably, the polysilicone based pressure sensitive adhesive provides a peel adhesion, preferably measured in accordance with Dow Corning Corp. corporate test method 0964A, of 300±200 g/cm (i.e. from 100 g/cm to 500 g/cm), more preferably 300±100 g/cm, still more preferably 300±50 g/cm; or 400±200 g/cm, more preferably 400±100 g/cm, still more preferably 400±50 g/cm; or 500±200 g/cm, more preferably 500±100 g/cm, still more preferably 500±50 g/cm; or 600±200 g/cm, more preferably 600±100 g/cm, still more preferably 600±50 g/cm; or 700±200 g/cm, more preferably 700±100 g/cm, still more preferably 700±50 g/cm; or 800±200 g/cm, more preferably 800±100 g/cm, still more preferably 800±50 g/cm; or 900±200 g/cm, more preferably 900±100 g/cm, still more preferably 900±50 g/cm.

In preferred embodiments polysilicone based pressure sensitive adhesives stabilize the pharmacologically active ingredient with respect to the formation of undesired degradation products. Formation of said degradation products can be suppressed especially when the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polysilicone based pressure sensitive adhesive is comparatively low.

According to this embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polysilicone based pressure sensitive adhesive is preferably at most 1.00 wt.-%, more preferably at most 0.80 wt.-%, still more preferably at most 0.70 wt.-%, yet more preferably at most 0.60 wt.-%, even more preferably at most 0.50 wt.-%, most preferably at most 0.40 wt.-%, and in particular at most 0.30 wt.-%, relative to the total weight of the adhesive layer (total per dry unit).

According to this embodiment, the adhesive layer preferably contains the pharmacologically active ingredient, the polysilicone based pressure sensitive adhesive and optional auxiliary substances (excipients) such as one or more percutaneous penetration enhancers, antioxidants, and the like.

According to this embodiment, the adhesive layer comprises the polysilicone based pressure sensitive adhesive preferably in combination with a permeation component, preferably comprising transcutol (diethylene glycol monoethylether), optionally in combination with dipropylene glycol. Preferably, the content of the transcutol and the optionally present dipropylene glycol is in each case independently of one another within the range of from 0.1 to 20 wt.-%, more preferably 0.2 to 15 wt.-%, still more preferably 0.5 to 10 wt.-%, yet more preferably 1.0 to 9.0 wt.-%, even more preferably 2.0 to 8.0 wt.-%, most preferably 3.0 to 7.0 wt.-%, and in particular 4.0 to 6.0 wt.-%, relative to the total weight of the adhesive layer. When dipropylene glycol is present as additional percutaneous penetration enhancer besides transcutol, the relative weight ratio of dipropylene glycol to transcutol is preferably within the range of from 10:1 to 1:10, more preferably 7.5:1 to 1:7.5, still more preferably 5:1 to 1:5, yet more preferably 4:1 to 1:4, even more preferably 3:1 to 1:3, most preferably 2:1 to 1:2, and in particular 1.5:1 to 1:1.5.

Preferred compositions of adhesive layers that comprise polysilicone based pressure sensitive adhesives are summarized as embodiments A¹ to A¹² in the table here below (all values as percentages relative to the total weight of the adhesive layer, total per dry unit):

[wt. %] A¹ A² A³ A⁴ A⁵ A⁶ pharmacologically active 0.01-1.00 0.03-0.95 0.04-0.95 0.05-0.90 0.06-0.90 0.08-0.85 ingredient (free base) silicone based pressure 59.00- 64.05- 69.05- 71.10- 73.10- 75.15- sensitive adhesive 99.99 99.97 99.96 99.95 99.94 99.92 percutaneous    0-30.00    0-25.00    0-20.00    0-18.00    0-16.00    0-14.00 penetration enhancer(s) other excipients    0-10.00    0-10.00    0-10.00    0-10.00    0-10.00    0-10.00 A⁷ A⁸ A⁹ A¹⁰ A¹¹ A¹² pharmacologically active 0.10-0.80 0.12-0.70 0.14-0.60 0.16-0.50 0.18-0.40 0.20-0.30 ingredient (free base) silicone based pressure 78.17- 81.30- 83.40- 85.50- 86.60- 87.70- sensitive adhesive 98.80 97.38 95.86 93.84 92.82 91.80 percutaneous  0.10-12.00  0.50-10.00 1.00-9.00 2.00-8.00 3.00-7.00 4.00-6.00 penetration enhancer(s) other excipients 1.00-9.00 2.00-8.00 3.00-7.00 4.00-6.00 4.00-6.00 4.00-6.00

It has been unexpectedly found that at concentrations within the range of from 0.20 to 0.30 wt.-%, relative to the total weight of the adhesive layer containing a silicone polymer (total per dry unit), the pharmacologically active ingredient can be formulated in dispersed form that exhibits a satisfactory shelf-life, i.e. that does not tend to recrystallize, and provides acceptable flux rates.

In another preferred embodiment, the pressure sensitive adhesive is an polyacrylate based pressure sensitive adhesive. Preferably, said polyacrylate based pressure sensitive adhesive forms a matrix in which the pharmacologically active ingredient is embedded. Polyacrylate based pressure sensitive adhesives are commercially available, e.g. under the trademark DuroTAK®, especially the 87 series, e.g. Duro-Tak® 87-202A; Duro-Tak® 87-208A; Duro-Tak® 87-502A; Duro-Tak® 87-503A; Duro-Tak® 87-2051; Duro-Tak® 87-2054; Duro-Tak® 87-2287; Duro-Tak® 87-2353; Duro-Tak® 87-2510; Duro-Tak® 87-2516; Duro-Tak® 87-4098; Duro-Tak® 87-4287; Duro-Tak® 87-9088; and Duro-Tak® 87-9301; or Duro-Tak® 387-2516.

When the pressure sensitive adhesive is an polyacrylate based pressure sensitive adhesive, e.g. Duro-Tak® 87-4287, it can contain a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, e.g. EUDRAGIT® E PO. According to this embodiment, the weight amount of EUDRAGIT® E PO is preferably 0.01 to 70 wt.-%, more preferably 10±9 wt.-%, or 20±10 wt.-%, or 30±10 wt.-%, or 40±10 wt.-%, or 50±10 wt.-% relative to the total combined weight of the acrylate pressure sensitive adhesive and the EUDRAGIT® E PO.

The polyacrylate based pressure sensitive adhesive may contain one or more acrylate homopolymers or one or more acrylate copolymers or mixtures thereof.

For the purpose of the specification, “(meth)acryl” shall refer to both, methacryl as well as acryl.

In a preferred embodiment, the adhesive layer comprises an acrylate copolymer comprising monomer units originating from monomers A which are selected from C₁₋₁₈-alkyl(meth)acrylates and monomers B which are copolymerizable with monomers A. Thus, the acrylate copolymer is derived from at least one monomer of the type of monomers A and at least one monomer of the type of monomers B.

In a preferred embodiment, the acrylate copolymer is derived from two different monomers (bipolymer), three different monomers (terpolymer) or four different monomers (quaterpolymer). Terpolymers are particularly preferred.

Preferred monomers A are selected from the group consisting of methyl (meth)acrylate, ethyl(meth)acrylate, propyl(meth)acrylate, butyl (meth)acrylate, pentyl(meth)acrylate, hexyl(meth)acrylate, cyclohexyl(meth)acrylate, octyl(meth)acrylate, isobornyl(meth)acrylate, and mixtures thereof. 2-Ethylhexyl(meth)acrylate is a preferred representative of an octyl(meth)acrylate.

Preferred monomers B are selected from the group consisting of 2-hydroxyethyl(meth)-acrylate, glyceryl mono(meth)acrylate, glycidyl(meth)acrylate, acrylamide, N,N-diethyl-(meth)acrylamide, 2-ethoxyethyl(meth)acrylate, 2-ethoxyethoxyethyl(meth)acrylate, tetra-hydrofuryl(meth)acrylate, vinyl acetate, N-vinyl pyrrolidone and mixtures thereof.

In a preferred embodiment, the acrylate copolymer is derived from a monomer composition comprising monomer units having at least one hydroxyl functional group, preferably selected from 2-hydroxyethyl(meth)acrylate and glyceryl mono(meth)acrylate.

In a particularly preferred embodiment, the acrylate copolymer is derived from a monomer composition comprising vinyl acetate, 2-ethylhexyl acrylate and 2-hydroxyethyl acrylate (terpolymer), optionally also comprising glycidyl methacrylate (quaterpolymer).

In another preferred embodiment, the acrylate copolymer that is contained in the adhesive layer does not comprise any monomer units having free hydroxyl functional groups.

Preferred embodiments B¹ to B⁸ of acrylate copolymers that are preferably contained in the adhesive layer are summarized in the table here below:

[wt.-%] B¹ B² B³ B⁴ B⁵ B⁶ B⁷ B⁸ vinyl acetate 5-55 10-50 15-45 17-40 17-40 17-40 17-40 17-40 2-ethylhexyl acrylate 45-95  50-90 55-85 60-80 55-75 55-75 55-75 55-75 2-hydroxyethyl acrylate 0-10   0-9.0   0-8.0   0-7.0 1.0-9.0 2.0-8.0 3.0-7.0 4.0-6.0 glycidyl methacrylate  0-5.0   0-4.0   0-3.0   0-2.0 — — — —

It has been found that different acrylate copolymers, i.e. acrylate copolymers originating from different comonomers and/or different relative amounts of comonomers, have a different influence on the chemical stability of the pharmacologically active ingredient, its maximal concentration in dispersed form at a sufficient shelf-life as well as its flux rate.

According to this embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polyacrylate based pressure sensitive adhesive is preferably at most 1.10 wt.-%, more preferably at most 1.05 wt.-%, still more preferably at most 1.00 wt.-%, yet more preferably at most 0.95 wt.-%, even more preferably at most 0.90 wt.-%, most preferably at most 0.85 wt.-%, and in particular at most 0.80 wt.-%, relative to the total weight of the adhesive layer (total per dry unit). According to this embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polyacrylate based pressure sensitive adhesive is preferably at least 0.35 wt.-%, more preferably at least 0.40 wt.-%, still more preferably at least 0.45 wt.-%, yet more preferably at least 0.55 wt.-%, even more preferably at least 0.60 wt.-%, most preferably at least 0.65 wt.-%, and in particular at least 0.70 wt.-%, relative to the total weight of the adhesive layer (total per dry unit).

According to this embodiment, the adhesive layer preferably contains the pharmacologically active ingredient, the polyacrylate based pressure sensitive adhesive and optional auxiliary substances (excipients) such as one or more percutaneous penetration enhancers, antioxidants, and the like.

According to this embodiment, the adhesive layer comprises the polyacrylate based pressure sensitive adhesive preferably in combination with a crystallization inhibitor, preferably comprising polyvinylpyrrolidone (e.g. Kollidon 25), and/or in combination with a permeation component, preferably comprising dipropylene glycol, optionally in combination with or oleyl alcohol. The combination of dipropylene glycol (permeation enhancer) with polyvinylpyrrolidone (crystallization inhibitor) is most preferred. Preferably, the content of the dipropylene glycol and the optionally present polyvinylpyrrolidone and oleyl alcohol, respectively, is in each case independently of one another within the range of from 0.1 to 20 wt.-%, more preferably 0.2 to 15 wt.-%, still more preferably 0.5 to 10 wt.-%, yet more preferably 1.0 to 9.0 wt.-%, even more preferably 2.0 to 8.0 wt.-%, most preferably 3.0 to 7.0 wt.-%, and in particular 4.0 to 6.0 wt.-%, relative to the total weight of the adhesive layer. When polyvinylpyrrolidone is present as crystallization inhibitor and/or oleyl alcohol is present as additional percutaneous penetration enhancer besides dipropylene glycol, the relative weight ratio of dipropylene glycol to polyvinylpyrrolidone and oleyl alcohol, respectively, is preferably within the range of from 10:1 to 1:10, more preferably 7.5:1 to 1:7.5, still more preferably 5:1 to 1:5, yet more preferably 4:1 to 1:4, even more preferably 3:1 to 1:3, most preferably 2:1 to 1:2, and in particular 1.5:1 to 1:1.5.

It has been surprisingly found that the combination of dipropylene glycol as permeation enhancer and polyvinyl pyrrolidone (Kollidon 25) as crystallization inhibitor provides particularly beneficial permeation performance of the pharmacologically active ingredient through the skin, particularly in adhesive layers containing polyacrylate based pressure sensitive adhesives.

Preferred compositions of adhesive layers that comprise polyacrylate based pressure sensitive adhesives are summarized as embodiments C¹ to C¹² in the table here below (all values as percentages relative to the total weight of the adhesive layer, total per dry unit):

[wt. %] C¹ C² C³ C⁴ C⁵ C⁶ pharmacologically active 0.15-1.35 0.17-1.30 0.25-1.25 0.30-1.20 0.35-1.15 0.40-1.10 ingredient (free base) acrylate based pressure 35.65- 42.17- 48.75- 55.30- 61.85- 63.40- sensitive adhesive 99.85 99.80 99.75 98.70 98.15 97.50 percutaneous    0-45.00    0-40.00    0-35.00  1.00-30.00  1.50-25.00  2.00-20.00 penetration enhancer(s) other excipients    0-18.00    0-16.50    0-15.00    0-13.50    0-12.00    0-10.50 C⁷ C⁸ C⁹ C¹⁰ C¹¹ C¹² pharmacologically active 0.45-1.05 0.50-1.00 0.55-0.95 0.60-0.90 0.65-0.85 0.70-0.80 ingredient (free base) acrylate based pressure 72.45- 76.50- 79.05- 81.60- 84.15- 86.70- sensitive adhesive 96.55 94.00 92.95 91.90 90.85 89.80 percutaneous  2.50-17.50  5.00-15.00  6.00-14.00  7.00-13.00  8.00-12.00  9.00-11.00 penetration enhancer(s) other excipients 0.50-9.00 0.50-7.50 0.50-6.00 0.50-4.50 0.50-3.00 0.50-1.50

It has been unexpectedly found that at concentrations within the range of from 0.50 to 1.00 wt.-%, relative to the total weight of the adhesive layer containing an acrylate polymer (total per dry unit), the pharmacologically active ingredient can be formulated in molecular dispersed form that exhibits a satisfactory shelf-life, i.e. that does not tend to recrystallize, and excellent flux rates. In this regard, the acrylate polymer is superior over the silicone polymer, particularly when it contains one or more percutaneous permeation enhancers selected from dipropylene glycol and oleyl alcohol and/or a crystallization inhibitor such as polyvinylpyrrolidone.

Preferably, the preferred acrylate copolymers according to any of embodiments B¹ to B⁸ can be contained in any of the preferred compositions of adhesive layers according to any of embodiments C¹ to C¹², i.e.: B¹C¹, B¹C², B¹C³, B¹C⁴, B¹C⁵, B¹C⁶, B¹C⁷, B¹C⁸, B¹C⁹, B¹C¹⁰, B¹C¹¹, and B¹C¹²; B²C¹, B²C², B²C³, B²C⁴, B²C⁵, B²C⁶, B²C⁷, B²C⁸, B²C⁹, B²C¹⁰, B²C¹¹, and B²C¹²; B³C¹, B³C², B³C³, B³C⁴, B³C⁵, B³C⁶, B³C⁷, B³C⁸, B³C⁹, B³C¹⁰, B³C¹¹, and B³C¹², B⁴C¹, B⁴C², B⁴C³, B⁴C⁴, B⁴C⁵, B⁴C⁶, B⁴C⁷, B⁴C⁸, B⁴C⁹, B⁴C¹⁰, B⁴C¹¹, and B⁴C¹², B⁵C¹, B⁵C², B⁵C³, B⁵C⁴, B⁵C⁵, B⁵C⁶, B⁵C⁷, B⁵C⁸, B⁵C⁹, B⁵C¹⁰, B⁵C¹¹, and B⁵C¹², B⁶C¹, B⁶C², B⁶C³, B⁶C⁴, B⁶C⁵, B⁶C⁶, B⁶C⁷, B⁶C⁸, B⁶C⁹, B⁶C¹⁰, B⁶C¹¹, and B⁶C¹²; and B⁷C¹, B⁷C², B⁷C³, B⁷C⁴, B⁷C⁶, B⁷C⁶, B⁷C⁷, B⁷C⁸, B⁷C⁹, B⁷C¹⁰, B⁷C¹¹, and B⁷C¹²; B⁸C¹, B⁸C², B⁸C⁴, B⁸C⁵, C⁸C⁶, B⁸C⁷, B⁸C⁸, B⁸C⁹, B⁸C¹⁰, B⁸C¹¹, and B⁸C¹².

In another preferred embodiment, the pressure sensitive adhesive contained in the adhesive layer comprises a polyisobutylene based pressure sensitive adhesive (e.g. Duro-Tak® 87-6908).

In still another preferred embodiment, the pressure sensitive adhesive contained in the adhesive layer comprises a styrenic rubber based pressure sensitive adhesive (polystyrene based pressure sensitive adhesive) (e.g.Duro-Tak® 87-6911).

In yet another preferred embodiment, the pressure sensitive adhesive contained in the adhesive layer comprises a mixture of two or more different pressure sensitive adhesives, e.g. a combination of two different polyacrylate based pressure sensitive adhesives, or a combination of an polyacrylate based pressure sensitive adhesive with a polysilicone based pressure sensitive adhesive; or a combination of an polyacrylate based pressure sensitive adhesive with a polyisobutylene based pressure sensitive adhesive or styrenic rubber based pressure sensitive adhesive; or a combination of a polysilicone based pressure sensitive adhesive with a polyisobutylene based pressure sensitive adhesive or styrenic rubber based pressure sensitive adhesive.

The layer of the pharmaceutical patch that contains the pharmacologically active ingredient or a portion thereof, i.e. the adhesive layer and the drug layer, respectively, may contain other pharmaceutical excipients that are conventionally contained in pharmaceutical patches.

Preferably, the adhesive layer comprises an antioxidant. Suitable antioxidants include but are not limited to alpha-tocopherol, butyl hydroxytoluene or n-propylgalat.

Preferably, the content of the antioxidant is within the range of from 0.01 to 10 wt.-%, more preferably 0.05 to 7.5 wt.-%, still more preferably 0.1 to 2.5 wt.-%, yet more preferably 0.5 to 1.5 wt.-%, even more preferably 0.7 to 1.3 wt.-%, most preferably 0.8 to 1.2 wt.-%, and in particular 0.9 to 1.1 wt.-%, relative to the total weight of the adhesive layer.

In a preferred embodiment, particularly when the adhesive layer does not contain the pharmacologically active ingredient (taking into account that after manufacture there typically is an exchange of the pharmacologically active ingredient between adjacent layers until an equilibrium has been reached), the area of the adhesive layer corresponds to the area of the pharmaceutical patch.

In another preferred embodiment, particularly when the adhesive layer contains the pharmacologically active ingredient, the total area of the adhesive layer can be divided into at least two portions of different composition: an inner area containing the pharmacologically active ingredient and an outer rim surrounding said inner area like a frame, said outer rim preferably not containing pharmacologically active ingredient. The area of said outer rim is not particularly limited but preferably amounts to e.g. about 5% of the total area of the adhesive layer.

In preferred embodiments, the pharmaceutical patch according to the invention exhibits satisfactory storage stability and shelf-life.

Preferably, after storage of the pharmaceutical patch for 3 month at 40° C. and 75% relative humidity in a sealed glass container, the degradation of the pharmacologically active ingredient does not exceed 5%, more preferably 4%, still more preferably 3%, yet more preferably 2%, and most preferably 1.5%.

Preferably, after storage of the pharmaceutical patch for 3 month at 5±3° C. in a sealed glass container, the degradation of the pharmacologically active ingredient does not exceed 4%, more preferably 3%, still more preferably 2%, yet more preferably 1.5%, most preferably 1%, and in particular 0.75%.

In a preferred embodiment of the pharmaceutical patch according to the invention

-   -   the pharmacologically active ingredient is present in form of         the free base, and/or     -   the concentration of the pharmacologically active ingredient in         the adhesive layer is at least 0.50 wt.-%, relative to the total         weight of the adhesive layer, and/or     -   the pharmaceutical patch upon application to the human skin         provides over a period of at least 6 hours release of the         pharmacologically active ingredient at a rate of at least 10         ng·cm⁻²·h⁻¹; and/or     -   the pharmaceutical patch provides plasma concentrations of the         pharmacologically active ingredient over a period of at least 6         hours upon consecutive application of a series of pharmaceutical         patches to the human skin, i.e. under steady state conditions         taking into account the depot effect of the skin, of at least         100 pg·ml⁻¹; and/or     -   the adhesive layer comprises a polymer that forms a matrix in         which the pharmacologically active ingredient is dispersed         (drug-in-adhesive); and/or     -   the adhesive layer comprises an polyacrylate based pressure         sensitive adhesive, preferably comprising an acrylate copolymer         derived from a monomer composition comprising vinyl acetate,         2-ethylhexyl acrylate and 2-hydroxyethyl acrylate (terpolymer),         optionally also comprising glycidyl methacrylate; and/or     -   the adhesive layer comprises a cationic copolymer based on         dimethylaminoethyl methacrylate, butyl methacrylate, and methyl         methacrylate; and/or     -   the adhesive layer contains one or more percutaneous penetration         enhancer(s), preferably selected from the group consisting of         transcutol (diethylene glycol monoethylether), oleyl alcohol,         dipropylene glycol and mixtures thereof; and/or     -   the adhesive layer contains one or more crystallization         inhibitors, preferably selected from polyvinylpyrrolidone (e.g.         Kollidon 25); and/or     -   the adhesive layer comprises an antioxidant in an amount within         the range of from 0.01 to 10 wt.-%.

In another preferred embodiment of the pharmaceutical patch according to the invention

-   -   the pharmacologically active ingredient is present in form of         the free base, and/or     -   the concentration of the pharmacologically active ingredient in         the adhesive layer is at least 0.20 wt.-%, relative to the total         weight of the adhesive layer, and/or     -   the adhesive layer comprises a polymer that forms a matrix in         which the pharmacologically active ingredient is dispersed         (drug-in-adhesive); and/or     -   the adhesive layer comprises a polysilicone based pressure         sensitive adhesive, and/or     -   the adhesive layer contains one or more percutaneous penetration         enhancer(s), preferably selected from the group consisting of         transcutol (diethylene glycol monoethylether), oleyl alcohol,         dipropylene glycol and mixtures thereof; and/or     -   the adhesive layer contains one or more crystallization         inhibitors, preferably selected from polyvinylpyrrolidone (e.g.         Kollidon 25).

The pharmaceutical patch according to the invention may be prepared by standard techniques for the manufacture of pharmaceutical patches. Such standard techniques are known to the skilled person (cf., e.g., H. A. E. Benson et al., Topical and Transdermal Drug Delivery: Principles and Practice, John Wiley & Sons; 2011; A. K. Banga, Transdermal and Intradermal Delivery of Therapeutic Agents: Application of Physical Technologies, CRC Press Inc; 2011).

Another aspect of the invention relates to a pharmaceutical patch as described above for use in the treatment of pain, preferably moderate to severe pain. The pain may be acute or chronic, central or peripheral, visceral or neuropathic.

The pharmaceutical patch according to the invention is suitable for use in the treatment of neuropathic pain, preferably chronic neuropathic pain such as painful diabetic neuropathy. Preferably, the pain is moderate, severe, or moderate to severe.

For the purpose of the specification, neuropathic pain is pain that originates from nerve damage or nerve malfunction. Preferably, the neuropathic pain is selected from acute neuropathic pain and chronic neuropathic pain. Neuropathic pain may be caused by damage or disease affecting the central or peripheral portions of the nervous system involved in bodily feelings (the somatosensory system). Preferably, the pharmaceutical patch according to the invention is for use in the treatment of chronic neuropathic pain or acute neuropathic pain, peripheral neuropathic pain or central neuropathic pain, mononeuropathic pain or polyneuropathic pain. When the neuropathic pain is chronic, it may be chronic peripheral neuropathic pain or chronic central neuropathic pain, in a preferred embodiment chronic peripheral mononeuropathic pain or chronic central mononeuropathic pain, in another preferred embodiment chronic peripheral polyneuropathic pain or chronic central polyneuropathic pain. When the neuropathic pain is acute, it may be acute peripheral neuropathic pain or acute central neuropathic pain, in a preferred embodiment acute peripheral mononeuropathic pain or acute central mononeuropathic pain, in another preferred embodiment acute peripheral polyneuropathic pain or acute central polyneuropathic pain. The invention also relates to the pharmacologically active ingredient according to the invention a physiologically acceptable salt thereof for use in the treatment of neuropathic pain as described above.

Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Fibromyalgia is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain. Accordingly, the pharmaceutical patch according to the invention is also suitable for the treatment of fibromyalgia. Aside from diabetic neuropathy and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic, and immune mediated disorders or physical trauma to a nerve trunk. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery.

The pharmaceutical patch according to the invention is also suitable for use in the treatment of nociceptive pain, preferably acute or chronic nociceptive pain. Preferably, the pain is moderate, severe, or moderate to severe.

Nociceptive pain refers to the discomfort that results when a stimulus causes tissue damage to the muscles, bones, skin or internal organs. For the purpose of the specification, nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being “thermal” (heat or cold), “mechanical” (crushing, tearing, etc.) and “chemical” (iodine in a cut, chili powder in the eyes). Nociceptive pain may also be divided into “visceral,” “deep somatic” and “superficial somatic” pain.

Visceral pain describes a type of nociceptive pain originating in the body's internal organs or their surrounding tissues. This form of pain usually results from the infiltration of harmful cells, as well as the compression or extension of healthy cells. Patients suffering from visceral pain tend to feel generally achy, as this pain tends to not be localized to a specific area. Cancer is a common source of visceral pain.

Somatic pain is nociceptive pain that results from some injury to the body. It's generally localized to the affected area and abates when the body repairs the damage to that area. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly-localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or superficial tissues, and is sharp, well-defined and clearly located.

According to the invention, nociceptive pain is preferably classified chronic if it has occurred for at least 3 months. Preferably, the chronic nociceptive pain is selected from chronic visceral pain, chronic deep somatic pain and chronic superficial somatic pain.

Preferred causes of nociceptive pain according to the invention include broken or fractured bones, bruises, burns, cuts, inflammation (from infection or arthritis), and sprains. Thus, nociceptive pain includes post-operative pain, cancer pain, low back pain, and inflammatory pain.

In preferred embodiments, the pain to be treated is selected from the group consisting of pain being or being associated with panic disorder [episodic paroxysmal anxiety] [F41.0]; dissociative [conversion] disorders [F44]; persistent somatoform pain disorder [F45.4]; pain disorders exclusively related to psychological factors [F45.41]; nonorganic dyspareunia [F52.6]; other enduring personality changes [F62.8]; sadomasochism [F65.5]; elaboration of physical symptoms for psychological reasons [F68.0]; migraine [G43]; other headache syndromes [G44]; trigeminal neuralgia [G50.0]; atypical facial pain [G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndrome without pain [G54.7]; acute and chronic pain, not elsewhere classified [G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris, unspecified [120.9]; other specified disorders of nose and nasal sinuses [J34.8]; other diseases of pharynx [J39.2]; temporomandibular joint disorders [K07.6]; other specified disorders of teeth and supporting structures [K08.8]; other specified diseases of jaws [K10.8]; other and unspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; other specified diseases of anus and rectum [K62.8]; pain in joint [M25.5]; shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhere classified [M53.3]; spine pain [M54.]; radiculopathy [M54.1]; cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain in thoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified [M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders, not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis, unspecified [M79.2]; pain in limb [M79.6]; other specified disorders of bone [M89.8]; unspecified renal colic [N23]; other specified disorders of penis [N48.8]; other specified disorders of male genital organs [N50.8]; mastodynia [N64.4]; pain and other conditions associated with female genital organs and menstrual cycle [N94]; mittelschmerz [N94.0]; other specified conditions associated with female genital organs and menstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat [R07.0]; chest pain on breathing [R07.1]; pericardial pain [R07.2]; other chest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal and pelvic pain [R10]; acute abdomen pain [R10.0]; pain localized to upper abdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized to other parts of lower abdomen [R10.3]; other and unspecified abdominal pain [R10.4]; flatulence and related conditions [R14]; abdominal rigidity [R19.3]; other and unspecified disturbances of skin sensation [R20.8]; pain associated with micturition [R30]; other and unspecified symptoms and signs involving the urinary system [R39.8]; headache [R51]; pain, not elsewhere classified [R52]; acute pain [R52.0]; chronic intractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified [R52.9]; other complications of cardiac and vascular prosthetic devices, implants and grafts [T82.8]; other complications of genitourinary prosthetic devices, implants and grafts [T83.8]; other complications of internal orthopedic prosthetic devices, implants and grafts [T84.8]; other complications of internal prosthetic devices, implants and grafts, not elsewhere classified [T85.8]; wherein the information in brackets refers to the classification according to ICD-10.

Preferably, the pharmaceutical patch is designed for application to the skin for a period of least 1 day, more preferably at least 2 days, most preferably at least 3 days or at least 3.5 days, and in particular 3 days, 3.5 days, 4 days or 7 days. Thus, according to this embodiment, continuous administration of the pharmacologically active ingredient can be achieved by removing a used pharmaceutical patch after the predetermined period has expired and replacing it by a fresh pharmaceutical patch.

In a preferred embodiment, the pharmaceutical patch is designed for application to the skin for an application period A, followed by a treatment period T during which no pharmaceutical patch is applied to the skin. Thus, according to this embodiment, continuous administration of the pharmacologically active ingredient can be achieved by removing a used pharmaceutical patch after the application period A has expired and replacing it by a fresh pharmaceutical patch after the treatment period has expired as well. It has been surprisingly found that the pharmacological half life t_(1/2) of the pharmacologically active ingredient is comparatively high so that its pharmacological effect lasts for a long time after administration has been interrupted or terminated. Preferred durations of application period A and treatment period T are summarized as embodiments D¹ to D¹⁷ in the table here below:

[days] D¹ D² D³ D⁴ D⁵ D⁶ D⁷ D⁸ D⁹ D¹⁰ D¹¹ D¹² D¹³ D¹⁴ D¹⁵ D¹⁶ D¹⁷ A 1 1 2 2 1 3 2 3 3 1 4 2 4 3 4 4 3.5 T 1 2 1 2 3 1 3 2 3 4 1 4 2 4 3 4 3.5

The locations of the skin to which the pharmaceutical patch according to the invention is to be applied are not particularly limited. Preferably, the pharmaceutical patch according to the invention is applied to the skin of the breast or the skin of the back.

In a preferred embodiment, the pharmaceutical patches according to the invention are repeatedly applied to the same location on the skin, i.e. after a first pharmaceutical patch has been used and needs to be replaced by a second pharmaceutical patch in order to maintain the desired pharmacological effect, said second pharmaceutical patch is preferably applied to the same location on the skin to which said first pharmaceutical patch was applied before.

In another preferred embodiment, particularly when the patient has a sensitive skin, the pharmaceutical patches according to the invention are applied to the different locations on the skin, i.e. after a first pharmaceutical patch has been used and needs to be replaced by a second pharmaceutical patch in order to maintain the desired pharmacological effect, said second pharmaceutical patch is preferably applied to a location on the skin differing from the location on the skin to which said first pharmaceutical patch was applied before.

The pharmaceutical patch according to the invention is for administration to the skin of an mammal, preferably of a human (pediatrics or adults).

The following examples further illustrate the invention but are not to be construed as limiting its scope.

For the purpose of the specification, “API” refers to the pharmacologically active ingredient, unless expressly stated otherwise in form of its free base.

For the purpose of the specification, “DEGR1”, “DEGR2”, “DEGR3” and “DEGR4” are identified degradation products of the API. DEGR2 has been confirmed as being non-toxic.

EXAMPLES Peel Strength Working Instruction

The peel strength is the force, measured in Newton, that must be exerted to remove the patch with a defined velocity from a stainless steel test plate.

Equipment and Materials

Tensile testing device (e.g. Zwick BT1-FR2.5TN.D14) including PC/application

Adequate load cell (e.g. 100 N)

Grips enabling measurement in 90° angle

Peeling apparatus (Sliding table), for measuring at 90° angle

Stainless steel test plate eg. V4A-AISI 316L

Separation aid: adhesive tape (e.g. tesafix 4963)

Cleaning agent: acetone

Die cut and die cut form (25 mm width)

Sample Preparation

25 mm wide stripes are die cut out of the patches, which are equilibrated to the climatic measuring conditions (23° C.±3° C./50%±10% r.h.) for at least 2 h prior to measurement.

Test Procedure

The 100 N load cell and the sliding table including the stainless steel testing plate are installed. The test plate is cleaned with acetone.

After the separation aid is affixed to the patch, the release liner is removed completely from the patch and the patch is adhered to the stainless steel plate without pressure, air bubbles or wrinkles. The separation aid is then fixed into the clamp of the tensile testing device in such a way that the patch is peeled off of the test plate in a 90° angle running a test velocity of 300 mm/min. The measurement has to be carried out in a timeframe of 30 to 60 seconds after adhering the sample to the test plate.

Evaluation of the Data

The standard procedure comprises 6 samples. The average value among the mean forces occurred within the measurement range is reported as N/25 mm.

Example 1

Patches with a layer sequence protective layer/adhesive layer/protective layer and differing in the formulation of the adhesive were prepared as follows:

Adhesives Used:

-   Duro-Tak 87-9301: 36.90 wt.-% solids; non-functional acrylic (no     hydroxyl, no carboxyl groups) -   Durotak 87-2287: 51.00 wt.-% solids; copolymer of vinyl acetate     (28%), 2-ethylhexyl-acrylate (67%), hydroxyethyl acrylate (4.9%) and     glycidyl methacrylate (0.1%)) -   Durotak 87-4098: 39.66 wt.-% solids; copolymer of     2-ethylhexylacrylate and vinyl acetate -   BIO PSA 7-4503 59.40 wt.-% solids; silicone adhesive,     non-functional, non-reactive, especially with amino groups.

Adhesive formulations of API at 1 wt.-% and 3 wt.-% in different adhesives were prepared in 20 mL vials and mixed on a jar roller. API at 1 wt.-% and 3 wt.-% in Duro-Tak 87-2287 (Ex. 1-3 and 1-4) were found to be insoluble. The other acrylate-based adhesive formulations were used to cast one sheet on a silicone coated polyester or polyethylene film (Loparex Primeliner® FLS release liner). Silicone-based adhesive formulations (Ex. 1-7 and 1-8) were cast onto a fluoropolymer coated polyester film (3M Scotchpak® 1022 release liner). A Gardco Automatic Drawdown machine was used to spread the adhesive at a thickness to target 100 g/m². The sheet was dried for five minutes at room temperature, then for seven minutes at 92° C. It was laminated with another sheet of the respective protective layer. The sheets were visually examined to verify API solubility, and checked for crystallization. The sheets were cut into round patches (3.9 cm²), stored at room temperature in polypropylene ziplock bags and were checked for crystallization formation with time.

Ingredients of adhesive layer [g]¹ ₎ (dry wt.- Ex. 1-1 Ex. 1-2 Ex. 1-3 Ex. 1-4 Ex. 1-5 Ex.1-6 Ex.1-7 Ex. 1-8 %)²⁾ form.1 form.2 form.3 form.4 form.5 form.6 form.7 form.8 API free base 0.05 (1) 0.15 (3) 0.05 (1) 0.15 (3) 0.05 (1) 0.15 (3) 0.05 (1) 0.15 (3) acrylic polymer 13.41 13.14 — — — — — — adhesive (99) (97) (DT87-9301) acrylic polymer — — 9.71 9.51 — — — — adhesive (99) (97) (DT87-2287) acrylic polymer — — — — 12.48 12.23 — — adhesive (99) (97) (DT87-4098) silicone adhesive BIO — — — — — — 12.48 (99) 12.23 (97) PSA 7-4503 additional 0.25 (−) 0.25 (−) 0.50 (−) 0.50 (−) 0.25 (−) 0.25 (−) — — toluene additional 0.25 (−) 0.25 (−) 0.50 (−) 0.50 (−) 0.25 (−) 0.25 (−) — — isopropanol solubility of API soluble soluble insoluble insoluble soluble soluble soluble soluble in adhesive appearance of clear cloudy — — clear cloudy some some casted sheet undissolved undissolved API API ¹⁾adhesive composition (5 g batch) after mixing; ²⁾composition of adhesive layer after drying

Example 2

According to the procedure of Example 1, further patches containing transcutol, oleyl alcohol or dipropylene glycol as additives were prepared. The final adhesive formulations and results are summarized here below:

Ingredients of adhesive layer [g]¹⁾ (dry wt.-%)²⁾ Ex. 2-1 Ex. 2-2 Ex. 2-3 Ex. 2-4 Ex. 2-5 Ex.2-6 API free base 0.05 (1) 0.05 (1) 0.05 (1) 0.05 (1) 0.05 (1) 0.05 (1) acrylic polymer adhesive (DT87-9301) 12.74 (94) 12.74 (94) 12.74 (94) — — — silicone adhesive BIO PSA 7-4503 — — —  7.91 (94)  7.91 (94)  7.91 (94) transcutol 0.25 (5) — — 0.25 (5) — — oleyl alcohol — 0.25 (5) — — 0.25 (5) — dipropylene glycol — — 0.25 (5) — — 0.25 (5) solubility of API in adhesive mixture soluble soluble soluble soluble soluble insoluble appearance of casted sheet clear clear clear clear clear — ¹⁾adhesive composition (5 g batch) after mixing; ²⁾composition of adhesive layer after drying

An in-vitro permeation study was performed with the adhesive formulations of the patches to show permeation of drug through synthetic membranes. The in-vitro experiments were conducted using Hanson Microette Franz Cell apparatus. The Franz-diffusion Cell consists of a donor compartment and a receiver compartment. A donut-shaped dosage wafer (inside diameter 15 mm) was fixated on top of each membrane and approximately 300 mg of the adhesive formulation were applied on top of the membrane to top the dosage wafer compartment. The membrane was sandwiched between the two compartments. A 40% aqueous PEG-400 solution (vol.-% PEG-400) was used as the receiving medium. The diffusion cells temperature was maintained at 32.5° C.±0.5° C. At predetermined times (2, 4, 6, 8, 12 and 24 hours) samples (aliquots of 500 μl) were withdrawn from the receiving compartment and immediately replaced by the same volume of fresh receiver medium. The permeation area (effective surface of sample well) was 1.76 cm² and the volume of the individual Franz Cell was 7 mL.

The synthetic membranes selected were: Nylon μm, Polysulfone, 0.45 μm, Cellulose acetate, 0.45 μm and SilTech (non-porous, silicone).

Flux studies with all five adhesive formulations were conducted using a Nylon membrane. The permeability results expressed in terms of cumulative amount (Q; pg/cm²) and flux (μg/cm²×h) are summarized here below:

Q per Total Flux Q Permeated Surface Area¹⁾ Flux = dQ/dT Example Time (μg) (μg/cm²) (μg/cm² h) 2-1 24 h 9.60 5.45 0.20 2-2 24 h 0.0 0.0 0.00 2-3 24 h 24.60 13.98 0.44 2-4 24 h 11.80 6.70 0.44 2-5 24 h 0.70 0.40 0.03 ¹⁾effective area of sample well: 1.76 cm²

Ex. 2-3 exhibits the best permeation through Nylon membranes.

Based on these results, a comparative flux study on the adhesive formulation of Ex. 2-3 using Nylon, Polysulfone, Cellulose acetate and SilTech (silicone) membranes was performed. The nylon membrane was run in duplicate to verify the reproducibility of permeation through this membrane. A summary of the results is presented in the table below:

Total Q Q per Flux Permeated Surface Area¹⁾ Flux = dQ/dT Membrane Time (μg) (μg/cm²) (μg/cm² h) Polysulfone 24 h 23.08 13.12 0.40 Nylon 24 h 20.74 11.78 0.35 Nylon 24 h 20.53 11.67 0.36 Cellulose acetate 24 h 17.09 9.71 0.39 Sil-Tech (SiliconE) 24 h 15.61 8.87 0.38 ¹⁾effective area of sample well: 1.76 cm²

As a result, nylon and cellulose acetate produced the most controlled results, that is, membranes showing the lowest permeation which would potentially be indicative of an ex vivo model. These membranes represent opposite polarities cellulose acetate being highly polar and porous (0.45 μm) and silicone being non-polar and non-porous. The other 3 membranes exhibited a high initial permeation and significant tailing off which indicates the membrane is not rate-controlling, but merely a membrane that allows dissolution of the drug from the adhesive matrix.

Example 3

Patches were prepared from the adhesive composition of the patch according to Ex. 2-3 (Ex. 3-1) and from six further adhesive compositions containing transcutol, oleyl alcohol and/or dipropylene glycol as additives.

The adhesive formulations were prepared in 20 mL vials and mixed on a jar roller. The formulations were used to cast one sheet on a silicone coated polyester or polyethylene film (Loparex Primeliner® FLS release liner). A Gardco Automatic Drawdown machine was used to spread the adhesive at a thickness to target 100 g/m². The sheet was dried for five minutes at room temperature, then for seven minutes at 92° C. It was laminated with a polyester laminate (3M Scotchpak® 9754 Surface layer, polyester film with an ethylene vinylacetate copolymer heat seal layer). Some 3.9 cm² round patches were cut from each sheet and packaged in heat sealed foil pouches.

The patches were visually examined to verify API solubility, and checked for crystallization. The sheets were stored at room temperature in polypropylene ziplock bags and were checked for crystallization formation with time.

The final adhesive formulations and results are summarized here below:

Ingredients of adhesive layer [g] (dry wt.-%) Ex. 3-1 Ex. 3-2 Ex. 3-3 Ex. 3-4 Ex. 3-5 Ex. 3-6 Ex. 3-7 API free base 0.05 (1) 0.05 (1)  0.05 (1)  0.05 (1) 0.05 (1) 0.05 (1) 0.05 (1) acrylic polymer 12.74 11.07 10.45 11.07 11.07 11.07 10.45 adhesive (DT87-9301) (94) (89) (84) (89) (89) (89) (84) transcutol — — — 0.25 (5) — — — oleyl alcohol — — — — 0.25 (5) — — dipropylene glycol 0.25(5) 0.50 (10) 0.75 (15) 0.25 (5) 0.25 (5) 0.25 (5) 0.25 (5) polyvinyl pyrrolidone — — — — — 0.25 (5)  0.50 (10) (Kollidon 25) solubility of API in soluble soluble soluble soluble soluble soluble soluble adhesive mixture appearance of casted sheet directly after clear clear clear clear clear clear clear production appearance of casted clear cloudy, clear clear clear clear cloudy, sheet after 7 days uneven uneven

According to Example 2, a comparative flux study was conducted on the patches using cellulose acetate and silicone membranes.

The results are depicted in FIGS. 1 and 2 as well as in the tables here below.

Cellulose Membrane:

Q per Total Q Permeated Surface Area¹⁾ Flux = dQ/dT Example Flux Time (μg) (μg/cm²) (μg/cm² h) 3-1 24 h 4.10 2.33 0.19 3-1 24 h 7.15 4.06 0.18 3-3 24 h 0.53 0.30 0.02 3-4 24 h 7.35 4.17 0.17 3-5 24 h 26.90 15.28 0.64 3-6 24 h 23.17 13.16 0.77 ¹⁾effective area of sample well: 1.76 cm²

Sil-Tech (Silicone) Membrane:

Q per Total Q Permeated Surface Area¹⁾ Flux = dQ/dT Example Flux Time (μg) (μg/cm²) (μg/cm² h) 3-1 24 h 7.38 4.19 0.15 3-1 24 h 7.26 4.13 0.14 3-3 24 h 8.63 4.90 0.21 3-4 24 h 6.18 3.51 0.13 3-5 24 h 16.31 9.27 0.37 3-6 24 h 20.49 11.64 0.39 ¹⁾effective area of sample well: 1.76 cm²

The results above indicate that Examples 3-5 and 3-6 show the best flux profiles when using both polar (cellulose acetate) and non-polar (silicone) membranes although the flux is higher with the cellulose acetate membranes.

Example 4

In accordance with Example 3, a patch was prepared from the adhesive composition according to the patch of Example 2-4, a fluoropolymer coated polyester film (3M Scotchpak® 1022) as protective layer and a polyester laminate (3M Scotchpak® 9754, polyester film with an ethylene vinylacetate copolymer heat seal layer) as surface layer.

A comparative study was conducted to evaluate the permeation behavior of API from the transdermal patches according to Examples 3-5, 3-6 and 4-1 through artificial skin constructs in comparison with two solutions (solution A: 300 μg/mL API in ethanol/DMSO/PEG 200=8:1:1; solution B: saturated solution of API in PEG 400).

Although the performance of the two solutions was better than the performance of the transdermal patches, these tests revealed that the pharmacologically active ingredient, when being contained in a pharmaceutical patch, can also penetrate into and through artificial skin. Furthermore, these tests indicate that pharmaceutical patches containing the pharmacologically active ingredient in an polyacrylate based pressure sensitive adhesive (drug-in-adhesive) are superior with respect to skin permeation performance over pharmaceutical patches containing the pharmacologically active ingredient in a polysilicone based pressure sensitive adhesive (drug-in-adhesive).

Example 5

Chemical stability testing was conducted with the patches of Examples and 3-5, 3-6 and 4. The conditions and detected amounts of impurities DEGR1 and DEGR2 are summarized here below:

Storing conditions Assay Impurity Impurity Ex. Timepoint [° C./% r.h.] [%] DEGR1 [%] DEGR2 [%] 3-5 start —/— 105.48 1.12 0.33 1 month 40/75 103.97 1.25 0.59 6 days 60/— 105.61 1.44 0.88 4 start —/— 108.33 n.d. 0.36 1 month 40/75 104.79 n.d. 0.40 6 days 60/— 108.77 n.d. 0.41 3-6 start —/— 106.58 1.15 0.32 1 month 40/75 105.35 1.28 0.42 6 days 60/— 105.82 1.34 0.56 n.d.: not detected; r.h.: relative humidity

As DEGR2 itself exhibits pharmacological activity and is non-toxic, it can be concluded from the above data that formulation 4 is storage stable, while the storage stability of formulations 3-5 and 3-6 is not satisfactory.

Example 6

The patches according to the previous Examples showed some re-crystallization of the matrices containing 1 wt.-% of API. In order to develop non-recrystallizing maximum API loads, variations of the patches according to Examples 3-5, 3-6 and 4-1 containing varying amounts of API were prepared according to the following procedure.

API in form of the free base is dissolved in isopropanol/toluene (1:1). The solution is sonicated, the other ingredients are added and the mixture is stirred overnight. A Gardco Automatic Drawdown machine is used to spread the adhesive composition at a thickness of 100 g/m² (unless stated otherwise) on a protective layer. The laminate is dried for ten minutes at room temperature and for 10 minutes at 70° C. before it is laminated with a sheet of Surface layer and cut to the desired size (9 cm² unit). The resulting patches were tested microscopically for recrystallization at 5 storing conditions after 1, 2 and 4 weeks.

-   Storing conditions: a) 2-8° C.     -   b) 40° C./75% relative humidity, open to air     -   c) 40° C./75% relative humidity, sealed     -   d) 25° C./160% relative humidity, sealed -   Protective layer: silicone coated polyethylene or polyester film     (Loparex Primeliner® FLS), used for the acrylate-based adhesives     -   fluoropolymer coated polyester film (3M Scotchpak® 1022), used         for the silicone-based adhesives -   Surface layer: polyester laminate (3M Scotchpak® 9754, polyester     film with an ethylene vinylacetate copolymer heat seal layer)

physicochemically Excipients API stable after 4 weeks at Example (dry wt.-%) (dry wt.-%) all conditions tested 6-1 Bio-PSA 4503/Transcutol (94/5)) 1 no 6-2 Bio-PSA 4503/Transcutol (94.5/5)) 0.5 no 6-3 Bio-PSA 4503/Transcutol (94.6/5)) 0.4 no 6-4 Bio-PSA 4503/Transcutol (94.7/5)) 0.3 no 6-5 Bio-PSA 4503/Transcutol (94.8/5)) 0.2 yes 6-6 DT87-9301/Oleyl alcohol/DPG (89/5/5) 1 no 6-7 DT87-9301/Oleyl alcohol/DPG (89.1/5/5) 0.9 no 6-8 DT87-9301/Oleyl alcohol/DPG (89.2/5/5) 0.8 no 6-9 DT87-9301/Oleyl alcohol/DPG (89.3/5/5) 0.7 no 6-10 DT87-9301/Oleyl alcohol/DPG (89.5/5/5) 0.5 yes 6-11 DT87-9301/PVP/DPG (88.5/5/5) 1.5 no 6-12 DT87-9301/PVP/DPG (88.75/5/5) 1.25 no 6-13 DT87-9301/PVP/DPG (89/5/5) 1 no 6-14 DT87-9301/PVP/DPG (89.25/5/5) 0.75 yes 6-15 DT87-9301/PVP/DPG (89.5/5/5) 0.5 yes PVP: polyvinyl pyrrolidone (Kollidon 25); DPG: dipropylene glycol

It can be concluded from the above data that in polyacrylate based adhesive layers a substantially higher API load can be achieved than in polysilicone based adhesive layers. Further, it can be concluded from the above data that in the presence of polyvinylpyrrolidone (PVP) a substantially higher API load can be achieved than in the presence of oleyl alcohol.

Example 7

Variations of the patch according to Ex. 6-14 (acrylic adhesive) were prepared according to the procedure of Example 6 using different antioxidants. The amount of impurity DEGR1 was determined:

Antioxidant Other excipients DEGR1 Ex. [1 wt.-%] [wt.-%] [%] 7-1 alpha-tocopherol DT87-9301/PVP/DPG/API 0.90 (88.25/5/5/0.75) 7-2 butyl hydroxytoluene DT87-9301/PVP/DPG/API 0.86 (88.25/5/5/0.75) 7-3 n-propylgalat DT87-9301/PVP/DPG/API 0.93 (88.25/5/5/0.75)

It can be concluded from the above data that compared to formulation 3-6 of Example 5 (1.15%), the addition of antioxidants reduces the initial content of undesired degradation product DEGR1. In this regard, the stabilizing effect of different antioxidants is equivalent to one another.

Example 8

Patches were prepared according to the procedure of Example 6, one based on acrylate adhesive Durotak 87-9301 and the others based on acrylate adhesive Durotak 87-4287. Further, the area weight of the adhesive was varied. The resulting patches were exposed to short term and stress stability testing and the amount of impurities DEGR1 and API was determined.

Formulation A: DT87-9301/PVP/DPG/API (89.25/5/5/0.75) Formulation B-1: DT87-4287/PVP/DPG/API (89.25/5/5/0.75) Formulation B-2: DT87-4287/PVP/DPG/BHT/API (88.25/5/5/1.00/0.75)

Durotak 87-4287 (40 wt.-% solids, copolymer of vinyl acetate (17-40%), 2-ethylhexylacrylate (55-75%) and hydroxyethyl acrylate (5.2%)).

area Start 1 month 40° C./75% r.h. 6 days/60° C. weight adhesive Batch size DEGR1 DEGR1 DEGR1 Ex. Form. [g/m ₂ ] [g] [wt.-%] [wt.-%] [wt.-%] 8-1 A 100 180 0.95 not tested not tested 8-2 B-1 100 40 0.21 1.06 1.30 8-3 B-1 55 40 0.15 0.70 0.85 8-4 B-2 100 40 0.19 0.77 0.99 8-5 B-2 55 40 0.14 0.58 0.71 8-6 B-2 100 140 0.19 not tested 0.63 8-7 B-2 55 140 0.17 1.06 0.57

It becomes evident from the above table that the change from acrylic adhesive Durotak 87-9301 to Durotak 87-4287 led to a significantly decreased level of DEGR1 after manufacturing. The amount of DEGR1 is further dependent on the area weight and thickness of the adhesive.

The patches according to Example 8-7 were chosen for further short term and accelerated stability studies:

RRT 0.55, RRT 0.59, RRT 0.31 and RRT 0.40 are unknown impurities characterized by a specific HPLC retention time RRT RRT RRT RRT Sum Time point/ Assay DEGR1 DEGR2 0.55 0.59 0.31 0.40 Sum all unknown conditions [%] [wt.-%] [wt.-%] [wt.-%] [wt.-%] [wt.-%] [wt.-%] [wt.-%] [wt.-%] Start 123.16 0.17 0.00 0.00 0.00 0.00 0.00 0.17 0.00 1 month 101.67 1.06 0.18 0.09 0.00 0.00 0.00 1.32 0.09 40° C./75% r.h. 3 months 103.75 1.10 0.14 0.00 0.00 0.00 0.00 1.23 0.00 40° C./75% r.h. 4.5 months 96.5 1.13 0.23 0.06 0.05 0.00 0.08 1.55 0.18 40° C./75% r.h. Start 123.16 0.17 0.00 0.00 0.00 0.00 0.00 0.17 0.00 1 month 95.45 0.50 0.06 0.05 0.00 0.00 0.00 0.61 0.05 2-8° C. 2 months 98.48 0.61 0.00 0.00 0.00 0.00 0.00 0.61 0.00 2-8° C. 3 months 106.73 0.61 0.06 0.00 0.00 0.00 0.00 0.67 0.00 2-8° C. 4.5 months 97.30 0.56 0.08 0.05 0.05 0.00 0.00 0.74 0.10 2-8° C.

It can be concluded from the above data that the formation of degradation product DEGR1 during manufacture and storage can be suppressed by

-   -   replacing Durotak 87-9301 by Durotak 87-4287;     -   reducing the thickness of the adhesive layer (100 g/m²->55         g/m²); and     -   adding antioxidants (e.g. BHT 1%).

Example 9

According to the procedure of Example 6, patches were prepared from the acrylic adhesive compositions given in the table here below. The resulting patches were tested microscopically for recrystallization after 4 weeks storing at 40° C./75% relative humidity, open to air.

physicochemically Excipients (dry wt.-%) stable Ex. DT87-4287 PVP DPG BHT API (crystal free) 9-1 89.25 5.00 5.00 — 0.75 yes 9-2 88.25 5.00 5.00 1.00 0.75 yes 9-3 88.00 5.00 5.00 1.00 1.00 no 9-4 87.75 5.00 5.00 1.00 1.25 no 9-5 87.50 5.00 5.00 1.00 1.50 no PVP: polyvinyl pyrrolidone (Kollidon 25); DPG: dipropylene glycol; BHT: butylhydroxy toluene

It can be concluded from the above data that when replacing Durotak 87-9301 by Durotak 87-4287 the API load cannot be further increased.

Example 10

According to the procedure of Example 6, patches were prepared from the silicone adhesive compositions given in the table here below. The resulting patches were tested microscopically for recrystallization after 4 weeks storing at 40° C./75% relative humidity, open to air.

Excipients (dry wt.-%) BIOPSA physicochemically stable Ex. 7-4503 transcutol PVP API (crystal free) 10-1 94.50 5.00 — 0.50 no 10-2 94.60 5.00 — 0.40 no 10-3 94.70 5.00 — 0.30 no 10-4 94.80 5.00 — 0.20 yes 10-5 89.00 5.00 5.00 1.00 no 10-6 89.50 5.00 5.00 0.50 no 10-7 89.60 5.00 5.00 0.40 no 10-8 89.70 5.00 5.00 0.30 yes

The patches according to Examples 10-4 and 10-8 were exposed to short term and stress stability testing. The amount of impurities DEGR1 and API was determined at different times.

1 month 40° C./75% 6 7 area weight Batch Start r.h. days/60° C. months/RT adhesive size DEGR1 DEGR2 DEGR1 DEGR1 DEGR1 Ex. [g/m²] [g] [wt.-%] [wt.-%] [wt.-%] [wt.-%] [wt.-%] 10-4 100 40 n.d. 0.18 n.d. n.d. — 10-8 100 40 0.24 0.23 0.38 n.d. n.d. n.d.: not detected

It can be concluded from the above data that this formulations exhibits excellent storage stability and shelf-life.

Example 11

Patches containing acrylic adhesive and silicone adhesive were prepared according to the procedure of Example 6. The amount of impurity DEGR1 was detected and the resulting patches were tested microscopically for recrystallization at 5 different storing conditions.

Storing conditions: a) 2-8° C.

-   -   b) 40° C./75% relative humidity, open to air     -   c) 40° C./75% relative humidity, sealed     -   d) 25° C./60% relative humidity, sealed

physico- chemically area stable after Excipients (dry wt.-%) weight 4 weeks at all DEGR1 DT87- BIOPSA adhesive conditions Start Ex. 4287 7-4503 API [g/m²] tested [wt.-%] 11-1 49.85 49.85 0.30 55 no 0.85 11-2 49.80 49.80 0.40 55 no 0.60 11-3 49.75 49.75 0.50 55 no 0.43 11-4 49.70 49.70 0.60 55 no 0.50

It can be concluded from the above data that two-component-formulation systems did neither provide advantages with regards to increased API load as compared to one-component silicone systems nor lower initial DEGR1 levels as compared to one-component-acrylate systems.

Example 12 Studies on Hairless Rats

In accordance with Example 3, laminates were prepared from the following acrylate adhesive compositions:

-   Solution 12A: Ethanol:DMSO:Lipoxol (PEG) 8:1:1 with API hemicitrate;     dose as indicated in the table below, concentration variable (volume     constant); and -   Solution 12B: Solution of API hemicitrate or free base in PEG400;     dose as indicated in the table below, concentration variable (volume     constant); -   Patch 12C: 89 wt.-% DT87-9301, 5 wt.-% dipropylene glycol, 5 wt.-%     polyvinyl pyrrolidone, 1 wt.-% API free base (dry wt.-%); and -   Patch 12D: 89.25 wt.-% DT87-4287, 5 wt.-% dipropylene glycol, 5     wt.-% polyvinyl pyrrolidone, 1 wt.-% butylhydroxy tolulol, 0.75     wt.-% API free base (dry wt.-%); and -   Patch 12E: 94.8 wt.-% Bio-PSA 7-4503, 5 wt.-% Transcutol, 0.2 wt.-%     API free base (dry wt.-%)

Patches of different sizes (3, 5, 12, 12.5 and 25 cm²) were cut from the laminate.

The analgesic efficacy of the patches was investigated in comparison to the efficacy of a topically applied PEG 400 solution of API (600 μg/mL) in the burning ray (tail flick) test on the rat by the method of D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941). Female hairless rats (OFA hr/hr, Charles River USA) weighing approx. 200 g were used. The animals were placed individually in special test cages and the base of the tail was exposed to a focused ray of heat from an electric lamp. The lamp intensity was adjusted such that the time from switching on the lamp to sudden jerking away of the tail (pain latency) was 3-5 seconds in untreated animals. Before topical administration of the drug-containing plaster or solution, the animals were pretested twice in the course of five minutes and the mean of these measurements was calculated as the pretest mean.

The pain measurement and the plasma concentrations were determined at different points in time after application of the plaster or solution (see table below).

The analgesic action was determined as the increase in the pain latency (% MPE) according to the following formula: [(T1−T0)/(T2−T0)]*100. In this, T0 is the latency time before and T1 the latency time after administration of the substance, T2 is the maximum exposure time (12 sec).

Study no. 1 Study no. 2 Study no. 3 Study no. 4 Species Female hairless rats OFA hr/hr (Charles River USA) Animals 36 20 32 32 (12 per group) (8 per group and 4 (8 per group) (8 per group) control animals) Vehicle Ethanol:DMSO:Lipoxol PEG 400 PEG 400 and PEG 400 + SEDDS (8:1:1) (Solution 12B) Patch 12C Patch 12D + 12E (Solution 12A) Dose 50 μg/kg 375 μg/kg 300 μg/kg 1029 μg/kg API hemicitrate 100 μg/kg API hemicitrate API API PEG400 API hemicitrate 200 μg/kg 1500 μg/kg 25 cm² TDS 1029 μg/kg API hemicitrate API (2060 μg) API SEDDS Vehicle only 12.5 cm² TDS 12.5 cm² TDS (1030 μg) (2763 μg) 5 cm² TDS 25 cm² TDS (412 μg) (2591 μg) Admin. 0.5 mL/kg 0.5 mL/kg 0.5 mL/kg for group 1 180 μL/Animal via Finn Chamber (3 cm²) Treatment 24 hours 24 hours 24 hours 30 hours duration Tail-flick 2 and 24 h 2, 6, 24, 29 and 2, 6, 24, 29 and 2, 6, 12 (solutions only), 48 h 51 h 24, 29 and 51 h PK 2.25, 4, 6, 10, 2.25, 4, 6.25, 10, 2.25, 4, 6.25, 10, 2.25, 4, 6.25, 10, 24.25, 24.25, 26, 30 and 24.25, 26, 30, 34 24.25, 26, 30, 34 26, 30, 34 and 51.25 h 34 h and 48.25 h and 51.25 h SEDDS—Self-Emulsifying Drug Delivery System

a) Study No. 1

The compositions of the solutions that were applied to the different groups are summarized in the table here below. The results of the tail-flick test and the plasma concentration measurements are depicted in FIG. 3.

dose AUC_(0-t) F group vehicle and amount [μg/animal] C_(max) [ng/mL] [h · ng/mL] t_(last) [h] [T/R] ref. API free base (i.v.) 32 ^(A)  11.7 ± 0.940 16.1 ± 1.91 12-24 — (Sprague-Dawley)  (8%) (12%) 1 102 μg/kg; 16 ^(B) 0.425 ± 0.230 6.33 ± 2.30 30-34 76% API hemicitrate (54%) (36%) 2 52 μg/kg; 8.3 ^(B) 0.240 ± 0.080 4.28 ± 1.09 34 99% API hemicitrate (33%) (25%) 3 188 μg/kg; 30 ^(B) 1.48 ± 1.26 15.5 ± 7.12 30-34 99% API hemicitrate (85%) (46%) ^(A) Body weight = 160 g/animal ^(B) Body weight = 200 g/animal

Based on the pharmacokinetic data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)

It becomes evident from the above tables that the bioavailability of the API hemicitrate in Ethanol:DMSO:Lipoxol (8:1:1 v/v/v) was 100% after dermal application compared to intravenous administration. Further, a dose-proportional increase of AUC_(0-t) was found.

b) Study No. 2

The compositions of the solutions that were applied to the different groups are summarized in the table here below. The results of the tail-flick test and the plasma concentration measurements are depicted in FIG. 4.

Group vehicle dose of API [μg] 1 PEG 400 (12 cm² patch)  300 μg/kg (API hemicitrate) 2 PEG 400 (12 cm² patch) 1500 μg/kg (API free base)

c) Study No. 3

The composition of the patches and the solution that were applied to the different groups are summarized in the table here below. The results of the tail-flick test and the plasma concentration measurements are depicted in FIGS. 5 to 7.

Group vehicle/amount dose of API free base [μg] 1 PEG 400, 0.5 mL/kg¹⁾ 300 μg/kg¹⁾ 2 25 cm² patch (82.4 μg/cm²) 2,060 3 12.5 cm² patch (82.4 μg/cm²) 1,030 4 5 cm² patch (82.4 μg/cm²)   412 ¹⁾body weight: approx. 200 g

Based on the pharmacological data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)

Dose¹⁾ C_(max) AUC_(0-t) F Ex. [μg/kg] [ng/mL] [h · ng/mL] t_(last) [h] [Ex./ref.] 12-2 10,300  1.02 ± 0.380 (37%) 18.9 ± 5.86 (31%) 51.25 1.8% 12-3 5,150 0.432 ± 0.201 (46%) 8.47 ± 1.06 (13%) 51.25 1.6% 12-4 2,060 0.274 ± 0.217 (79%) 4.17 ± 1.53 (37%) 51.25 2.0% reference²⁾ 160  11.7 ± 0.940 (79%) 16.1 ± 1.91 (12%) 12-24 ¹⁾body weight: approx. 200 g/animal ²⁾reference: Sprague-Dawley rat, API free base intravenous

It becomes evident from the above tables that the bioavailability of the patches is approximately 1.8%. Further, a dose-proportional (area-proportional) increase of AUC_(0-t) was found.

FIG. 8 shows the dose dependency of the patches of study no. 3.

d) Study No. 4

The composition of the patches and the solution that were applied to the different groups are summarized in the table here below.

Group vehicle dose of API free base [μg] 1 PEG 400 (3 cm² Finn chamber) 180 μg (1029 μg/kg) 2 SEDDS (3 cm² Finn chamber) 180 μg (1029 μg/kg)

The results of the tail-flick test and the plasma concentration measurements are depicted in FIGS. 9 and 10.

FIG. 9 shows the tail-flick data and plasma concentrations of API free base in PEG400 or SEDDS applied in Finn chambers to approximately 3 cm².

FIG. 10 shows the tail-flick data and plasma concentrations of API free base after application of Patch 12D (acrylate) and Patch 12E (silicone).

e) Overview (Studies No. 2, 3 and 4)

The absolute bioavailability of API free base and API hemicitrate is summarized in the table here below.

dose [μg/ AUC_(0-t) F study group animal] C_(max) [ng/mL] [h · ng/mL] t_(last) [h] [T/R] ref. API free base (i.v.)  32 ^(A)  11.7 ± 0.940 16.1 ± 1.91 12-24   (Sprague-Dawley)  (8%) (12%) 2 PEG/API hemicitrate  60 ^(A) 0.47 ± 0.12 9.88 ± 1.73 34-48.25  32% (750 μg/mL; 60%) (26%) (17%) PEG/API free base 300 ^(A) 8.51 ± 5.17  128 ± 26.8 48.25  82% (3000 μg/mL; 60%) (61%) (21%) 3 PEG/API free base  60 ^(A) 1.88 ± 1.33 22.3 ± 11.8 34-51.25  71% (600 μg/mL; 12%) (71%) (53%) 4 PEG/API free base 180 0.208 ± 0.129  2.66 ± 0.654 51.25 2.8% (Finn (1000 μg/mL; 180 μL) (62%) (25%) chamber) SEEDS/API free base 180 0.171 ± 0.020 3.26 ± 1.01 51.25 3.5% (1000 μg/mL; 180 μL) (12%) (31%) body weight: approx. 200 g/animal

Based on the pharmacokinetic data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)

It becomes evident from the above table that the bioavailability of the API hemicitrate is approximately 2.5 fold lower compared to the API free base in PEG400. The bioavailability of API free base in human SEDDS is slightly higher compared to the PEG formulation (Finn chamber).

Further, a dose-proportional increase of AUC_(0-t) for the API free base in PEG400 was observed.

FIG. 11 shows the dose dependency of patches according to studies no. 2 and 3.

The absolute bioavailability of API free base after application of Patch 12C (acrylate), Patch 12D (acrylate) and Patch 12E (silicone) is summarized in the table here below.

dose [μg/ AUC_(0-t) F study group animal] C_(max) [ng/mL] [h · ng/mL] t_(last) [h] [T/R] ref. API free base (i.v.) (Sprague-  32 ^(A) 11.7 ± 0.940 16.1 ± 1.91 12-24 — Dawley)  (8%) (12%) 3 Acrylate: 25 cm² Patch 12C 2060 1.02 ± 0.380 18.9 ± 5.86 51.25 1.8% (82 μg/cm²; (37%) (31%) 2060 μg/Animal) Acrylate: 12.5 cm² Patch 12C 1030 0.432 ± 0.201  8.47 ± 1.06 51.25 1.6% (82 μg/cm²; 1030 μg/Animal) (46%) (13%) Acrylate: 5 cm² Patch 12C  412 0.274 ± 0.217  4.17 ± 1.53 51.25 1.9 % (82 μg/cm²; 412 μg/Animal) (79%) (37%) 4 Acrylate: 12.5 cm² Patch 12D  528 1.03 ± 0.413 23.5 ± 7.05 51.25 8.5% 42 μg/cm²; 528 μg/Animal) (40%) (30%) Silicone: 25 cm² Patch 12E  500 0.824 ± 0.491  16.8 ± 7.43 51.25 6.4% (20 μg/cm²; 500 μg/Animal) (60%) (44%) body weight: approx. 200 g/animal

Based on the pharmacokinetic data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)

It becomes evident from the above table that the bioavailability of acrylate Patch 12C is approximately 1.8%. The bioavailability of API free base in Patch 12D is slightly higher compared to the silicone Patch 12E (8.5% vs. 6.4%).

Further, a dose-proportional (area-proportional) increase of AUC_(0-t) was observed.

The absolute bioavailability and flux of API free base for different topical vehicles is summarized in the table here below.

dose [μg/ AUC_(0-t) F size flux ^(A)) vehicle group animal] [h · ng/mL] [T/R] [cm²] [ng/cm²/h] Solution 12A 52 μg/kg; 8.3 —  99% ~12 28 Ethanol:DMS API hemicitrate O:Lipoxol 102 μg/kg; 16 —  76% ~12 42 (8:1:1) API hemicitrate 188 μg/kg; 30 —  99% ~12 103 API hemicitrate Solution 12B API hemicitrate 60 —  32% ~12 66 PEG 400 (750 μg/mL; 60%) API free base 300 —  82% ~12 852 (3000 μg/mL; 60%) API free base 60 —  71% ~12 148 (600 μg/mL; 12%) API free base 180 — 2.8% ~3 71 (1000 μg/mL; 20%) Finn chamber SEDDS API free base 180 — 3.5% ~3 87 (1000 μg/mL) Finn Chamber Patch 12C 25 cm², 2060 μg API 2060 18.9 1.8% 25 60 (82.4 μg/cm²) free base per animal Acrylate 12.5 cm², 1030 μg API 1030 8.47 1.6% 12.5 54 patch free base per animal 5cm², 412 μg API free 412 4.17 1.9% 5 67 base per animal Patch 12D 12.5 cm², 528 μg API 528 23.5 8.5% 12.5 150 (42.2 μg/cm²) free base per animal Acrylate patch Patch 12E 25 cm², 500 μg API 500 16.8 6.4% 25 54 (20 μg/cm²) free base per animal Silicone patch ^(A)) based on total patch load or load in solution Flux = (F · Dose_(Dermal))/(Size_(Dermal) · Time)

Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)×100%.

It becomes evident from the above table that highest flux rates were derived from highly dosed PEG400 solution and from patch 12D (acrylate).

Example 13 Overview of Bioavailability and Flux of API in Hairless Rats

Patches with vehicles 13-1 to 13-12 were prepared and tested as described above in Example 12:

-   13-1 Acrylate Patch 12D: 89.25 wt.-% DT87-4287 (acrylate), 5 wt.-%     dipropylene glycol, 5 wt.-% polyvinyl pyrrolidone, 1 wt.-%     butylhydroxy tolulol, 0.75 wt.-% API free base (dry wt.-%) -   13-2 44.75 wt.-% DT87-4287 (acrylate), 44.75 wt.-% Eudragit® EPO, 5     wt.-% Transcutol, 5 wt.-% Levulinic acid, 0.5 wt.-% API free base     (dry wt.-%) -   13-3 49.4 wt.-% DT87-4287 (acrylate), 49.4 wt.-% Eudragit® EPO, 1.2     wt.-% API free base (dry wt.-%) -   13-4 44.3 wt.-% DT87-4287 (acrylate), 44.3 wt.-% Eudragit® EPO, 10     wt.-% Transcutol, 1.4 wt.-% API free base (dry wt.-%) -   13-5 44.81 wt.-% DT87-4287 (acrylate), 44.81 wt.-% Eudragit® EPO, 10     wt.-% Levulinic acid, 0.38 wt.-% API free base (dry wt.-%) -   13-6 94.8 wt.-% Bio-PSA 7-4503 (silicone), 5 wt.-% Transcutol, 0.2     wt.-% API free base (dry wt.-%) -   13-7 85.0 wt.-% Bio-PSA 7-4503 (silicone), 13.5 wt.-% polyvinyl     alcohol, 1.5 wt.-% API free base (dry wt.-%) -   13-8 85.0 wt.-% Bio-PSA 7-4602/3 (silicone), 13.5 wt.-% polyvinyl     pyrrolidone, 1.5 wt.-% API free base (dry wt.-%) -   13-9 99.75 wt.-% DT87-6911 (styrene), 0.25 wt.-% API free base (dry     wt.-%) -   13-10 89.7 wt.-% DT87-6911 (styrene), 5 wt.-% Transcutol, 5 wt.-%     Levulinic acid, 0.3 wt.-% API free base (dry wt.-%) -   13-11 89.5 wt.-% DT87-6911 (styrene), 10 wt.-% Transcutol, 0.5 wt.-%     API free base (dry wt.-%) -   13-12 89.7 wt.-% DT87-6911 (styrene), 10 wt.-% Levulinic acid, 0.3     wt.-% API free base (dry wt.-%)

The absolute bioavailability of API free base and API hemicitrate is summarized in the table here below.

dose dura- AUC_(0-t) size [μg/ tion size [h · ng/ F flux ^(A)) norm. vehicle group animal] [h] [cm²] mL] [T/R] [ng/cm²/h] AUC_(0-t) 13-1 12.5 cm² à 42 μg/cm² 528 30 12.5 23.5 7.1% 108 1.6 API free base 520 24 15.1 13-2 3, 5 and 10 cm² à 29 μg/cm² 86 24 3 1.78 4.8% 58 0.72 API free base 145 5 2.94/3.61 290 10 9.80 13-3 5 cm² à 68 μg/cm² 341 24 5 6.46 3.6% 103 1.3 API free base 13-4 5 cm² à 76 μg/cm² API free base 382 24 5 5.30 2.7% 85 1.1 13-5 5 cm² à 22 μg/cm² API free base 111 24 5 5.42 9.4% 87 1.1 13-6 25 cm² à 20 μg/cm² API free base 500 30 25 16.8 6.4% 43 0.67 13-7 12.5 cm² à 80 μg/cm² 1000 24 12.5 3.66^(B)) 0.70% 23 0.29 API free base 13-8 12.5 cm² à 80 μg/cm² 1000 24 12.5 4.43^(B)) 0.85% 28 0.35 API free base 13-9 12.5 cm² à 14 μg/cm² 175 24 12.5 18.7 20% 119 1.5 API free base 13-10 5 cm² à 17 μg/cm² API free base 84 24 5 0.919 2.1% 15 0.18 13-11 5 cm² à 28 μg/cm² API free base 139 24 5 4.42 6.1% 71 0.88 13-12 5 cm² à 17 μg/cm² API free base 83 24 5 0.650 1.5% 10 0.13 ^(A)) based on total patch load or load in solution ^(B))AUC_(0-24h) Flux = (F · Dose_(Dermal))/(Size_(Dermal) · Time)

Based on the pharmacokinetic data, bioavailability F and flux rate of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference.

F=AUC _(dermal) /AUC _(intravenous)×dose_(intravenous)/dose_(dermal)×100%

Flux(ng/cm²/h)=(AUC _(dermal)×dose_(dermal))/(AUC _(intravenous)×size_(dermal)×duration)

It becomes evident from the above table that the flux of the styrene patch (13-9) was slightly higher but still comparable to the acrylate prototype (13-1). The silicone formulations 13-7 and 13-8 showed significantly reduced plasma levels.

None of the combinations of adhesives with enhancers demonstrate increased flux in comparison to the acrylate prototype (13-1). In contrast, levels were significantly reduced in some cases.

Example 14 Studies in Minipigs a) Study on Male Minipigs

According to Example 6, laminates were prepared from the following adhesive compositions:

-   i) acrylate-based adhesive composition:     -   88.25 wt.-% DT87-4287, 5 wt.-% dipropylene glycol, 5 wt.-%         polyvinyl pyrrolidone, 0.75 wt.-% API free base (dry wt.-%). For         the adhesive composition an area weight of 55 g/m² was selected. -   ii) silicone-based adhesive composition:     -   94.80 wt.-% Bio-PSA 7-4503, 5 wt.-% transcutol, 0.20 wt.-% API         free base (dry wt.-%). For the adhesive composition an area         weight of 100 g/m² was selected.

Patches of 100 cm² size were cut from the two laminates.

An animal study was conducted using eight male mini-pigs. In two periods, four different formulations of API free base were administered to the animals:

amount/concentration of dose Period formulation vehicle API free base [μg/animal] 1 A patch with acrylate-based adhesive 6 × 100 cm²/42.2 μg/cm² 25,320 B PEG 400 using Finn chamber (18 mm), 5 × 330 μL/1 mg/mL 1,650 application area: approx. 2.5-3.1 cm² 2 C patch with silicone-based adhesive 6 × 100 cm²/20 μg/cm² 12,000 D PEG 400, application area: 400 cm² 5 mL/1 mg/mL 5,000

Plasma concentrations of API free base were determined at different times after application of the formulations.

The resulting mean pharmacokinetic data are summarized in the table here below and in FIG. 12.

Dose C_(max) AUC_(0-t) AUC AUC_(t%) Formulation [μg/animal] [ng/mL] t_(max) [h · ng/mL] t_(last) [h · ng/mL] [%] T_(1/2,z) A 25320 0.137 33.0 9.06 132 9.50 95.5 24.9 B¹⁾ 1650 0.033 12.0 2.07 144 3.06 67.6 74.4 C²⁾ 12000 0.042 56.0  0.622  64 — — — D 5000 0.053 39.0 3.85 138 5.01 76.5 64.5 ¹⁾data of one animal only ²⁾n = 3

Based on the pharmacokinetic data, bioavailability F and flux rate of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference.

F=AUC _(dermal) /AUC _(intravenous)×dose_(intravenous)/dose_(dermal)×100%

Flux(ng/cm²/h)=(AUC _(dermal)×dose_(dermal))/(AUC _(intravenous)×size_(dermal)×duration)

Dose Formu- [μg/ AUC F size flux²⁾ lation animal] [h · ng/mL] [form./ref.] [cm²] [ng/cm² · h] A 25320 9.50 1.7% 600 10 C 12000 0.622 0.24%  600 0.7 D 5000 5.01 4.6% 400 8 reference¹⁾ 564 12.3 ¹⁾reference: intravenous dose of API free base: 40 μg/kg to 4 male pigs (3 were evaluated, mean body weight: 14.1 kg) ²⁾duration = 72 h

b) Study on Male and Female Minipigs

Patches were prepared as described above. An overview on the study is provided by the table below:

Study no. 1 (= Example 14a) Study no. 2 Species Male Göttinger SPF minipigs Female Göttinger SPF minipigs Animals 8 (4 per group) two periods with 4 weeks 16 (4 per group) washout Vehicle PEG 400 PEG 400 Patch 12D + Patch 12E Patch 12D + Patch 12E Dose Period 1: Period 1: A) Acrylate-Patch 12D: 6 × 100 cm² A) Control: two patch prototypes and (42.2 μg/cm²), 25320 μg/animal PEG 400 B) PEG: 5 × ~330 μL (Finn chamber a 3 cm²), B) Acrylate-Patch 12D: 6 × 100 cm² 1.65 mL (1000 μg/mL), 1650 μg/animal (41.1 μg/cm²), 24660 μg/animal Period 2: Period 2: C) Silicone-Patch 12E: 6 × 100 cm² C) Silicone-Patch 12E: 6 × 100 cm² (20.0 μg/cm²), 12000 μg/animal (20.3 μg/cm²), 12180 μg/animal D) PEG: 5 mL (1000 μg/mL), 5000 μg/animal D) PEG: 5 mL (3000 μg/mL), 15000 μg/animal Application size Patches: A) and C) = 600 cm² Patches: B) and C) = 600 cm² PEG solution: B) = 15 cm² and PEG solution: D) = ~300 cm² D) = ~300 cm² Treatment 72 hours 96 hours duration PK 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72 (=5 min 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, before removal), 84, 96, 108, 120, 132 and 84, 96 (=5 min before removal), 108, 144 h 120, 132, 144, 156 and 168 h

Male Minipigs Cf. Example 14a

The plasma concentrations of API free base after application of Patch 12D (acrylate) and Patch 12E (silicone) and PEG to male minipigs (Study no. 1) are displayed in FIG. 13.

The resulting mean pharmacokinetic data of Study no. 1 (male) are summarized in the table here below:

dose C_(max) AUC_(0-t) study group [μg/animal] [ng/mL] [h · ng/mL] t_(last) [h] F [TR] ref. i.v. API free base 564 4.86 ± 1.47 11.9 ± 1.33 36-48 — (male minipig) (30%) (11%) 1-A Acrylate: 600 cm² 25320 0.137 ± 0.036 9.06 ± 2.90 108-144    1.7% Patch 12D (26%) (32%) (42.2 μg/cm²; 25320 μg/animal) 1-C Silicone: 600 cm² 12000 0.042 ± 0.025 0.622 ± 0.524 60-72   0.24% Patch 12E (60%) (84%) (20.0 μg/cm²; 12000 μg/animal) 1-B PEG400: ~15 cm² 1650 0.033 ^(A) 2.07 ^(A) 144  <5.9%^(A) Finn Chamber (1.65 mL a 1 mg/mL = 1650 μg/ animal) 1-D PEG400: 5000 0.053 ± 0.012  3.85 ± 0.780 117-144    3.6% ~300 cm² (5 mL a (23%) (20%) 1 mg/mL = 5000 μg/animal) ^(A)one out of four animals showed concentrations >LLOQ (lower limit of quantification)

Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)×100%.

It becomes evident from the above table that the bioavailability of API free base in acrylate Patch 12D is 7-fold higher compared to the silicone patch (1.7% vs. 0.24%). Without wanting to be limited by theory, this could be a consequence of the insufficient adherence of the silicone patch to the skin compared to the acrylate patch.

Only one out of four animals showed concentrations>LLOQ after PEG400 in Finn chambers.

Female Minipigs

The plasma concentrations of API free base after application of Patch 12D (acrylate) and Patch 12E (silicone) and PEG to female minipigs (Study no. 2) are displayed in FIG. 14.

The resulting mean pharmacokinetic data of Study no. 2 (female) are summarized in the table here below:

dose C_(max) AUC_(0-t) F study group [μg/animal] [ng/mL] [h · ng/mL] t_(last) [h] [TR] ref. i.v. API free base 648 6.97 ± 1.17 11.4 ± 0.82 36-48 — (female minipig) (17%)  (7%) 2-B Acrylate: 600 cm² 24660 0.047 ± 0.010  3.93 ± 0.497 117-168 0.9% Patch 12D (21%) (13%) (41.1μg/cm²; 24660 μg/animal) 2-C Silicone: 600 cm² 12180 not not — — Patch 12E calculated^(A) calculated^(A) (20.3 μg/cm²; 12180 μg/animal) 2-D PEG400: 15000 0.038 ± 0.013 3.21 ± 1.10 108-168 1.2% ~300 cm² (5mL á (34%) (34%) 3 mg/mL = 15000 μg/animal) ^(A)one out of four animals showed concentrations >LLOQ

Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)×100%.

It becomes evident from the above table that with the silicone patch, due to the very low plasma concentrations in three out of four animals no PK parameters were calculated. Without wanting to be limited by theory, this may be an effect of the low adhesiveness.

The bioavailability of API free base in female animals was 2-3 times lower compared to the study in male animals which might be a consequence of the skin lesions in male minipigs.

SUMMARY

The absolute bioavailability and flux of API free base for different topical vehicles is summarized in the table below:

study dose_(Dermal) AUC_(0-t) F size time flux ^(B)) no. group [μg/animal] [h · ng/mL] [TR] [cm²] [h] [ng/cm²/h] 1 Acrylate Patch 25320 9.06  1.7% 600 72      9.9 (male) 12D: 600 cm² Silicone Patch 12E: 12000 0.622 0.24% 600 72      0.7 600 cm² PEG400: 15 cm2 Finn Chamber 1650 <<2.07^(A) <<5.9%^(A) ~15 72 <<90^(A) (1 mg/mL) PEG400: 300 cm² 5000 3.85  3.6% ~300 72      8.4 (1mg/mL) 2 Acrylate Patch 24660 3.93  0.9% 600 96      3.9 (female) 12D: 600 cm² Silicone Patch 12E: 12180 n.c. n.c. ^(A) 600 96 n.c. ^(A) 600 cm² PEG400: 300 cm² 15000 3.21  1.2% ~300 96      6.3 (3 mg/mL) ^(A)one out of four animals showed concentrations >LLOQ ^(B)) based on total patch load or load in solution Flux = (F · Dose_(Dermal))/(Size_(Dermal) · Time)

Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUC_(dermal)/AUC_(intravenous)×dose_(intravenous)/dose_(dermal)×100%.

It becomes evident from above table that in the minipig, penetration of API free base was not found for all tested formulations (reliable plasma concentration was measured only for the “painted” PEG400, Acrylate patch and Silicone patch in males only).

The females showed 2-3 fold lower plasma concentrations compared to the males, which might be a consequence of the skin lesions in male minipigs.

Plasma concentrations increased within the first 2 days after dermal application and thereafter a concentration plateau was observed until removal of the foil (solutions) or patch at 72 h/96 h.

The absolute bioavailability was low for all tested formulations (PEG400=3.6% male/1.2% female and Acrylate patch=1.7% male/0.9% female).

The face-to-face comparison of the patch types showed significantly lower performances of the Silicone patch, which might be a consequence of the insufficient adherence of the Silicone Patch to the skin compared to the Acrylate Patch.

Example 15 Ex Vivo Studies Across Pig Skin

The permeation of API free base across dermatomized pig skin (incl. stratum corneum) from the following patches has been investigated:

-   P1 Acrylate Patch 12D: 89.25 wt.-% DT87-4287 (acrylate), 5 wt.-%     dipropylene glycol, 5 wt.-% polyvinyl pyrrolidone, 1 wt.-%     butylhydroxy tolulol, 0.75 wt.-% API free base (dry wt.-%) -   P2 Silicone Patch 12E: 94.8 wt.-% Bio-PSA 7-4503 (silicone), 5 wt.-%     Transcutol, 0.2 wt.-% API free base (dry wt.-%) -   P3 99.75 wt.-% DT87-6911 (styrene), 0.25 wt.-% API free base (dry     wt.-%) -   P4 85.0 wt.-% Bio-PSA 7-4602/3 (silicone), 13.5 wt.-% polyvinyl     pyrrolidone, 1.5 wt.-% API free base (dry wt.-%) -   P5 49.4 wt.-% DT87-4287 (acrylate), 49.4 wt.-% Eudragit® EPO, 1.2     wt.-% API free base (dry wt.-%) -   P6 44.75 wt.-% DT87-4287 (acrylate), 44.75 wt.-% Eudragit® EPO, 5     wt.-% Transcutol, 5 wt.-% Levulinic acid, 0.5 wt.-% API free base     (dry wt.-%)

The results of ex vivo testing of patches P1 to P6 across dermatomized pig skin are summarized in the table below and in FIG. 16.

SUM (dermal patch receptor fluid dermis epidermis absorption) P1 Acrylate prototype 26.60 51.44 22.15 100.19 P2 Silicone prototype 35.90 62.80 18.47 117.17 P3 DT 87-6911 styrene 25.19 184.20 17.97 227.36 P4 Bio-PSA 7-4602/3 silicone/ 7.39 32.15 10.26 49.80 PVP P5 DT 87-4287 acrylate/ 13.96 59.84 9.16 82.96 Eudragit EPO 1:1 P6 DT 87-4287 acrylate/ 14.98 77.60 18.57 111.15 Eudragit EPO 1:1 + 5% Levulinic acid + 5% Transcutol

It becomes evident from FIG. 16 that the permeation across dermatomized pig skin does not reveal a significant improvement in comparison to the acrylate prototype patch, although the styrene prototype performed slightly better (while being in the same range). Furthermore, no increased permeation could be observed using Transcutol and Levulinic acid as enhancer combination.

Example 16 Permeation Testing Through EVA Membrane

In a series of experiments under comparable conditions, the permeation of the API from various patches across a synthetic EVA membrane was tested.

Patch 16-1 corresponds to 12E (silicone prototype). Patches 16-2 to 16-4 correspond to 12E (acrylate prototype).

The results are summarized in FIGS. 17 (PEG 400 as acceptor medium) and 18 (ammonium acetate buffer as acceptor medium).

Summarizing, both EVA-membrane permeation systems showed a permeation kinetic which could not be obtained by using human skin, however, data achieved from the two patch prototypes are in a comparable order and ratio as observed in hairless rats. Both buffer systems yielded a similar permeation performance of patches containing API free base. The data obtained with the ammonium acetate buffer were more sophisticated compared to the system with a PEG 400 solution as acceptor medium. Accordingly, the EVA-membrane permeation system using ammonium acetate buffer is suitable to compare patch formulations containing API free base.

Example 17 Compatibility Testing (Polymer Screening)

In a series of experiments under comparable conditions, patches of identical basic compositions but of different polymers were tested in terms of compatibility with the API free base. All patches contained 0.75 wt.-% of API free base.

The different polymers which were tested are summarized in the table below:

adhesive API (0.75 wt.-%) batch no. name description solvent solvent 17-1 DuroTak Acrylate-vinylacetate Ethyl acetate, Heptane, Isopropyl Isppropyl alcohol, 87-2054 (COOH) x-linked alcohol, Pentanedione, Toluene Toluene 17-2 DuroTak Acrylate (OH) Ethyl acetate, Hexane Isppropyl alcohol, 87-2510 Toluene 17-3 DuroTak Acrylate-vinylacetate Ethyl acetate, Heptane Isppropyl alcohol, 87-2051 (COOH) Toluene 17-4 DuroTak Acrylate (COOH) Ethyl acetate, Hexane Isppropyl alcohol, 87-2353 Toluene 17-5 DuroTak Acrylic-rubber hybrid Ethyl acetate, Heptane, Hexane Isppropyl alcohol, 87-502A (OH) Toluene 17-6 DuroTak Acrylic-rubber hybrid Ethyl acetate, Heptane, Hexane, Isppropyl alcohol, 87-503A (OH), x-linked Pentanedione Toluene 17-7 DuroTak Acrylate (OH), x- Ethyl acetate, Isopropyl alcohol, Isppropyl alcohol, 87-202A linked Methyl alcohol, Pentanedione Toluene 17-8 DuroTak Polyisobutylene Heptane Isppropyl alcohol, 87-6908 Toluene 17-9 DuroTak Styrenic rubber Toluene, Heptane Toluene 87-6911 17-10/ DuroTak Acrylate copolymer Ethyl acetate Isppropyl alcohol, 17-11 87-9301 Toluene 17-12/ DuroTak Acrylate-vinylacetate Ethyl acetate Isppropyl alcohol, 17-13 87-4287 (OH) Toluene 17-14 DuroTak Acrylate-vinylacetate Ethyl acetate, Ethyl alcohol, Isppropyl alcohol, 387-2516 (OH), x-linked Heptane, Methyl alcohol Toluene

All polyacrylate based adhesives showed no re-crystallisation of the API at start and after 6 days at 60° C. The styrenic rubber (17-9) as well as the isobutylene prototype (17-8) showed after the manufacturing and after 6 days at 60° C. re-crystallisation of the API.

The results of a stress stability testing of API free base containing wet polymer matrices at room temperature (RT) over 6 days are summarized in the table below:

API free base [%] DEGR1 [%] DEGR2 [%] 17-1 Start 105.0 — — 6 d RT 98.3 0.70 — 17-2 Start 98.3 5.70 — 6 d RT 103.2 5.27 0.07 17-3 Start 105.7 — — 6 d RT 113.1 0.76 — 17-4 Start 105.8 — — 6 d RT 108.3 2.25 — 17-5 Start 75.5 4.25 — 6 d RT 73.8 4.22 — 17-6 Start 72.0 3.12 — 6 d RT 68.4 2.89 0.13 17-7 Start 105.3 3.13 — 6 d RT 109.1 4.02 — 17-8 Start 83.1 — — 6 d RT 84.1 — — 17-9 Start 94.7 — — 6 d RT 94.1 — — 17-10 Start 107.5 0.45 — 6 d RT 104.6 0.52 — 17-12 Start 104.9 1.02 — 6 d RT 99.1 0.60 — 17-14 Start 97.3 0.73 — 6 d RT 83.3 0.60 —

The results of a stress stability testing of API free base containing patch samples at 60° C. over 6 days are summarized in the table below:

API free base [%] DEGR1 [%] DEGR2 [%] 17-1 Start 98.5 — — 6 d 60° C. 95.4 1.31 — 17-2 Start 93.2 4.29 0.21 6 d 60° C. 89.5 6.77 1.15 17-3 Start 97.0 — — 6 d 60° C. 97.0 0.74 — 17-4 Start 100.0 — — 6 d 60° C. 98.3 1.00 — 17-5 Start 95.5 3.53 0.39 6 d 60° C. 70.6 24.62  2.77 17-6 Start 93.5 2.64 0.42 6 d 60° C. 80.0 10.38  4.72 17-7 Start 96.3 0.74 — 6 d 60° C. 93.8 1.45 0.45 17-8 Start 98.3 — — 6 d 60° C. 98.3 0.18 — 17-9 Start 100.0 — — 6 d 60° C. 102.4 — — 17-10 Start 90.5 0.66 — 6 d 60° C. 91.8 0.90 — 17-11 Start 91.8 0.59 — 6 d 60° C. 95.9 0.81 — 17-12 Start 95.0 0.60 — 6 d 60° C. 95.1 1.14 0.42 17-13 Start 95.0 0.66 — 6 d 60° C. 96.7 1.13 0.30 17-14 Start 95.9 0.13 — 6 d 60° C. 98.3 0.68 0.28

The styrenic rubber DuroTak 87-6911 as well as the polyisobutylene prototypes DuroTak 87-6908 yielded formulations with very low amounts of impurities. The acrylate adhesives DuroTak 87-2051, as well as DuroTak 87-2353 showed the lowest degradation profiles of the acrylate formulations.

Example 18 Solubilizer Screening

In a series of experiments under comparable conditions, patches made of silicone adhesives and various solubilizers were tested in terms of compatibility with the API free base and the recrystallization tendency for the API free base.

An overview of the different batches which were prepared is given in the table below:

excipient API free base amount amount batch no. adhesive excipient [wt.-%] [wt.-%] 18-1 BioPSA 7-4503 PVP (Kollidon 25) 4.5 0.5 18-2 BioPSA 7-4503 PVP (Kollidon 25) 9.0 1.0 18-3 BioPSA 7-4503 PVP (Kollidon 25) 13.5 1.5 18-4 BioPSA 7-4503 Glycerol (anhydrous) 4.5 0.5 18-5 BioPSA 7-4503 Glycerol (anhydrous) 9.0 1.0 18-6 BioPSA 7-4503 Glycerol (anhydrous) 13.5 1.5 18-7 BioPSA 7-4503 Polyvinylalcohol (Mowiol 4-88) 4.5 0.5 18-8 BioPSA 7-4503 Polyvinylalcohol (Mowiol 4-88) 9.0 1.0 18-9 BioPSA 7-4503 Polyvinylalcohol (Mowiol 4-88) 13.5 1.5 18-10 BioPSA 7-4302/3 PVP (Kollidon 25) 4.5 0.5 18-11 BioPSA 7-4302/3 PVP (Kollidon 25) 9.0 1.0 18-12 BioPSA 7-4302/3 PVP (Kollidon 25) 13.5 1.5 18-13 BioPSA 7-4302/3 Glycerol (anhydrous) 4.5 0.5 18-14 BioPSA 7-4302/3 Glycerol (anhydrous) 9.0 1.0 18-15 BioPSA 7-4302/3 Glycerol (anhydrous) 13.5 1.5 18-16 BioPSA 7-4302/3 Polyvinylalcohol (Mowiol 4-88) 4.5 0.5 18-17 BioPSA 7-4302/3 Polyvinylalcohol (Mowiol 4-88) 9.0 1.0 18-18 BioPSA 7-4302/3 Polyvinylalcohol (Mowiol 4-88) 13.5 1.5 18-19 BioPSA 7-4602/3 PVP (Kollidon 25) 4.5 0.5 18-20 BioPSA 7-4602/3 PVP (Kollidon 25) 9.0 1.0 18-21 BioPSA 7-4602/3 PVP (Kollidon 25) 13.5 1.5 18-22 BioPSA 7-4602/3 Glycerol (anhydrous) 4.5 0.5 18-23 BioPSA 7-4602/3 Glycerol (anhydrous) 9.0 1.0 18-24 BioPSA 7-4602/3 Glycerol (anhydrous) 13.5 1.5 18-25 BioPSA 7-4602/3 Polyvinylalcohol (Mowiol 4-88) 4.5 0.5 18-26 BioPSA 7-4602/3 Polyvinylalcohol (Mowiol 4-88) 9.0 1.0 18-27 BioPSA 7-4602/3 Polyvinylalcohol (Mowiol 4-88) 13.5 1.5

Re-crystallization was tested at the start and after 6 days at room temperature (RT). Square-shaped and needle-shaped crystals could be detected. The results are summarized in the table below:

API free base amount start 6 days/RT batch no. [wt.-%] excipient [morphology] [morphology] 18-1 0.5 PVP (Kollidon 25) − − 18-2 1.0 PVP (Kollidon 25) + + [o] [o] 18-3 1.5 PVP (Kollidon 25) + + [o] [o] 18-4 0.5 Glycerol (anhydrous) + + [−] [−] 18-5 1.0 Glycerol (anhydrous) + + [−] [−] 18-6 1.5 Glycerol (anhydrous) + + [−] [−] 18-7 0.5 Polyvinylalcohol (Mowiol 4-88) + − [o] 18-8 1.0 Polyvinylalcohol (Mowiol 4-88) + (+) [o] [o] 18-9 1.5 Polyvinylalcohol (Mowiol 4-88) + (+) [o] [o] 18-10 0.5 PVP (Kollidon 25) − − 18-11 1.0 PVP (Kollidon 25) + + [−] [−] 18-12 1.5 PVP (Kollidon 25) + + [−] [−] 18-13 0.5 Glycerol (anhydrous) + + [−] [−] 18-14 1.0 Glycerol (anhydrous) + + [−] [−] 18-15 1.5 Glycerol (anhydrous) + + [−] [−] 18-16 0.5 Polyvinylalcohol (Mowiol 4-88) + + [−] [o] 18-17 1.0 Polyvinylalcohol (Mowiol 4-88) + + [o] [o] 18-18 1.5 Polyvinylalcohol (Mowiol 4-88) + + [o] [o] 18-19 0.5 PVP (Kollidon 25) − − 18-20 1.0 PVP (Kollidon 25) − − 18-21 1.5 PVP (Kollidon 25) − − 18-22 0.5 Glycerol (anhydrous) + + [−] [−] 18-23 1.0 Glycerol (anhydrous) + + [−] [−] 18-24 1.5 Glycerol (anhydrous) + + [−] [−] 18-25 0.5 Polyvinylalcohol (Mowiol 4-88) + + [−] [−] 18-26 1.0 Polyvinylalcohol (Mowiol 4-88) + + [−] [−] 18-27 1.5 Polyvinylalcohol (Mowiol 4-88) + + [−] [−] −: no crystals; +: crystals; (+): single crystals; [o]: square-shaped crystals; [−]: needle-shaped crystals

Two silicone adhesives (BioPSA 7-4503 and BioPSA 7-4603) in combination with either PVP or PVA showed promising results.

The results of a stress stability testing of API free base containing patch samples at 60° C. over 6 days are summarized in the table below:

API free base Assay [%] DEGR1 [%] DEGR2 [%] 18-1 Start 99.3 0.22 — 6 d 60° C. 101.0 0.35 0.32 18-2 Start 98.1 0.07 — 6 d 60° C. 99.5 0.28 0.26 18-3 Start 99.1 — — 6 d 60° C. 99.0 0.15 0.14 18-4 Start 99.0 0.25 — 6 d 60° C. 100.5 0.33 0.12 18-5 Start 99.1 0.20 — 6 d 60° C. 99.9 0.20 0.09 18-6 Start 100.0 — — 6 d 60° C. 100.7 0.08 0.06 18-7 Start 96.4 0.25 — 6 d 60° C. 99.9 0.28 0.09 18-8 Start 82.4 0.11 — 6 d 60° C. 84.0 0.14 0.06 18-9 Start 75.4 — — 6 d 60° C. 74.5 0.12 0.06 18-10 Start 96.3 0.08 — 6 d 60° C. 101.3 0.32 0.31 18-11 Start 101.5 0.92 — 6 d 60° C. 111.3 0.17 0.12 18-12 Start 101.8 — — 6 d 60° C. 99.7 0.19 0.11 18-13 Start 96.9 0.24 — 6 d 60° C. 100.9 0.28 0.10 18-14 Start 102.1 1.14 — 6 d 60° C. 98.7 0.12 0.09 18-15 Start 98.4 — — 6 d 60° C. 97.8 0.06 0.11 18-16 Start 100.7 0.15 — 6 d 60° C. 103.2 0.23 0.32 18-17 Start 63.9 0.29 — 6 d 60° C. 61.8 0.15 0.12 18-18 Start 104.6 — — 6 d 60° C. 98.9 0.08 0.09 18-19 Start 97.5 — — 6 d 60° C. 98.1 0.31 0.17 18-20 Start 100.3 0.99 — 6 d 60° C. 99.0 0.15 0.16 18-21 Start 96.1 — — 6 d 60° C. 96.5 0.17 0.27 18-22 Start 98.0 — — 6 d 60° C. 98.0 0.28 0.08 18-23 Start 93.5 1.43 — 6 d 60° C. 95.9 0.13 0.08 18-24 Start 99.8 — — 6 d 60° C. 101.1 0.05 0.08 18-25 Start 84.6 — — 6 d 60° C. 83.3 0.25 0.10 18-26 Start 96.6 1.47 — 6 d 60° C. 96.2 0.11 0.17 18-27 Start 84.9 — — 6 d 60° C. 84.3 0.11 0.26

All formulations containing 1.5% API free base and 13.5% hydrophilic polymer showed an acceptable degradation profile.

Example 19 Characterization of Polymer Screening Prototypes

In a series of experiments under comparable conditions, patches of identical basic compositions but of different polymers were tested in terms of recrystallization of the API free base and permeation across a synthetic EVA membrane.

An overview of the different batches which were prepared is given in the table below:

API free base batch no. adhesive amount [wt-%] 19-1 DuroTak 87-6908 (polyisobutylene) 0.75 19-2 DuroTak 87-6908 (polyisobutylene) 0.50 19-3 DuroTak 87-6908 (polyisobutylene) 0.25 19-4 DuroTak 87-6911 (styrenic rubber) 0.75 19-5 DuroTak 87-6911 (styrenic rubber) 0.50 19-6 DuroTak 87-6911 (styrenic rubber) 0.25 19-7 DuroTak 87-2051 (acrylate-vinylacetate) 0.75 19-8 DuroTak 87-2051 (acrylate-vinylacetate) 1.00 19-9 DuroTak 87-2051 (acrylate-vinylacetate) 1.25 19-10 DuroTak 87-2353 (acrylate) 0.75 19-11 DuroTak 87-2353 (acrylate) 1.00 19-12 DuroTak 87-2353 (acrylate) 1.25 19-13 DuroTak 87-4287 (acrylate) 0.75 (reference)

Re-crystallization was tested at the start and after 4 weeks at 25° C./60% r.h. (relative humidity) as well as 40° C./75% r.h. The results are summarized in the table below:

API free 4 weeks/ base 25° C./ 4 weeks/ batch content start 60% r.h. 40° C./75% r.h. no. [wt.-%] [morphology] [morphology] [morphology] 19-1 0.75 + + + [−] [−] [−] 19-2 0.50 + + + [−] [−] [−] 19-3 0.25 + + + [−] [−] [−] 19-4 0.75 + + + [o] [o] [o] 19-5 0.50 (+) + + [o] [o] [o] 19-6 0.25 − − − 19-7 0.75 − − − 19-8 1.00 − − − 19-9 1.25 − − −  19-10 0.75 − − −  19-11 1.00 − − −  19-12 1.25 − − − −: no crystals; +: crystals; [o]: square-shaped crystals; [−]: needle-shaped crystals

Re-crystallization occurred in the isobutylene as well as in the styrenic rubber adhesive at higher concentrations. Both acrylate adhesives showed no recrystallization events.

API free base containing patch samples were tested on assay and purity after manufacturing. The results are summarized in the table below:

19-13 19-1 19-2 19-3 19-4 19-5 19-6 19-7 19-8 19-9 19-10 19-11 19-12 (ref.) API free 88.9 80.8 49.5 98.4 89.6 106.9 98.5 99.7 101.3 98.4 100.5 99.3 110.5 base [%] DEGR1 0.06 0.08 0.15 / / / 0.16 0.14 0.12 0.19 0.16 0.14 0.66 [%] DEGR2 / / / 0.14 0.16 0.33 / / / / / / 0.18 [%]

The permeation through an EVA membrane was tested.

FIG. 19 shows the EVA membrane permeation testing of polyisobutylene formulations containing API free base (19-1, 19-2, 19-3) vs. an acrylate reference patch (19-13, composition 12D). All three API concentrations showed a lower flux rate over the EVA membrane compared to the reference patch 19-13.

FIG. 20 shows the EVA membrane permeation testing of styrenic rubber formulations containing API free base (19-4, 19-5, 19-6) vs. an acrylate reference patch (19-13, composition 12D). All three API concentrations showed a higher flux rate over the EVA membrane compared to the reference patch 19-13.

The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:

steady-state correlation steady-state flux adhesive interval [h] coefficient [r²] rate [μg/cm²/h] factor  19-13 DuroTak 87-4287 (acrylate) 8-72 0.999 0.036 1.00 (ref.) 19-1 DuroTak 87-6908 8-72 0.999 0.009 0.25 19-2 (polyisobutylene) 8-72 0.996 0.008 0.22 19-3 8-72 0.999 0.009 0.25 19-4 DuroTak 87-6911 (styrenic 6-22 1.000 0.081 2.25 19-5 rubber) 6-22 0.998 0.075 2.08 19-6 8-72 0.999 0.056 1.56 19-7 DuroTak 87-2051 (acrylate- 0-72 1.000 0.001 — 19-8 vinylacetate) 8-30 0.997 <0.001 — 19-9 22-46  0.999 0.001 —  19-10 DuroTak 87-2353 (acrylate) 22-46  0.997 <0.001 —  19-11 22-46  0.999 <0.001 —  19-12 22-46  0.997 <0.001 —

It becomes evident from the above table that the styrenic rubber polymer DuroTak 87-6911 shows increased permeation rate while being lower concentrated in comparison to an acrylate reference patch 12D.

Example 20 EVA Permeation Testing of Silicone Prototypes

Following silicone patches were tested:

excipient API free batch amount base amount no. adhesive excipient [wt.-%] [wt.-%] 18-7  BioPSA 7-4503 Polyvinylalcohol 4.5 0.5 (Mowiol 4-88) 18-8  BioPSA 7-4503 Polyvinylalcohol 9.0 1.0 (Mowiol 4-88) 18-9  BioPSA 7-4503 Polyvinylalcohol 13.5 1.5 (Mowiol 4-88) 18-19 BioPSA 7-4602/3 PVP (Kollidon 25) 4.5 0.5 18-21 BioPSA 7-4602/3 PVP (Kollidon 25) 13.5 1.5

The permeation through an EVA membrane was tested.

FIG. 21 shows the EVA membrane permeation testing of silicone/PVA formulations containing API free base (18-7, 18-8, 18-9) vs. an acrylate reference patch (19-13, composition 12D).

FIG. 22 shows the EVA membrane permeation testing of silicone/PVP formulations containing API free base (18-19, 18-21) vs. an acrylate reference patch (19-13, composition 12D).

The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:

correlation steady-state steady-state coefficient flux rate adhesive interval [h] [r²] [μg/cm²/h] factor 19-13 DuroTak 87-4287 19-72  0.999 0.047 1.00 (ref.) (acrylate) 18-7  BioPSA 7-4503 6-72 0.997 0.028 0.60 18-8  PVA 6-72 0.995 0.037 0.79 18-9  19-72  0.998 0.095 2.02 18-19 BioPSA 7-4602/3 30-72  0.996 0.048 1.02 18-21 PVP 8-72 0.999 0.108 2.30

It becomes evident from the above table that both, the silicone/PVA and the silicone/PVP formulation with 1.5% API free base shows increased permeation rate in comparison to an acrylate reference patch 12D.

Example 21 Solubility and Permeation of Acrylate Prototypes

In a series of experiments under comparable conditions, patches of identical basic compositions of two acrylate adhesives were tested in terms of saturation solubility of the API free base and permeation across a synthetic EVA membrane.

An overview of the different batches which were prepared is given in the table below:

batch no. adhesive API free base amount [wt.-%] 21-1 DuroTak ® 87-2353 3.0 21-2 DuroTak ® 87-2353 3.5 21-3 DuroTak ® 87-2353 4.0 21-4 DuroTak ® 87-2051 3.0 21-5 DuroTak ® 87-2051 3.5 21-6 DuroTak ® 87-2051 4.0

Re-crystallization was not observed at the start, and neither after 7 days at 25° C./60% r.h. (relative humidity) or 40° C./75% r.h. Even with 4% API free base in the polymers, the patch samples showed no re-crystallization over a time period of 7 days.

API free base containing patch samples were tested on assay and purity after manufacturing. The results are summarized in the table below:

19-13 21-1 21-2 21-3 21-5 24-7 21-6 (ref.) API free 99.1 100.6 108.3 99.6 99.5 100.6 110.5 base [%] DEGR1 / 0.02 / / 0.05 0.04 0.66 [%] DEGR2 0.07 0.04 / 0.05 0.06 0.05 0.18 [%]

The permeation through an EVA membrane was tested.

FIG. 23 shows the EVA membrane permeation testing of Duro Tak® 87-2353 formulations containing API free base (21-1, 21-2, 21-3) vs. an acrylate reference patch (19-13, composition 12D). All tested DuroTak® 87-2353 showed a significant lower flux rate compared to the reference patch.

FIG. 24 shows the EVA membrane permeation testing of DuroTak® 87-2051 formulations containing API free base (21-5, 21-6, 24-7) vs. an acrylate reference patch (19-13, composition 12D). All tested DuroTak® 87-2051 showed a significant lower flux rate compared to the reference patch.

The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:

steady-state steady-state correlation flux rate adhesive interval [h] coefficient [r²] [μg/cm²/h]  19-13 DuroTak 87-4287 19-72  0.999 0.037 (ref.) (acrylate) 21-1 DuroTak 87-2353 8-72 0.998 0.001 21-2 8-54 0.996 0.001 21-3 8-54 0.999 0.001 21-5 DuroTak 87-2051 30-72  0.999 0.001 24-7 30-72  0.995 0.001 21-6 8-46 0.998 0.001

Both acrylate adhesive have acidic functional groups. It is likely that an interaction with API free base occurs so that a saturation of the polymer with the API free base could not reached even at a high concentration of 4% API free base. The low flux rate observed is a consequence of the non-saturated system.

Example 22 Eudragit® EPO Loading in Duro Talc® 87-4287

In a series of experiments under comparable conditions, patches made of acrylate DuroTak 87-4287 and Eudragit EPO were tested in terms of adhesiveness.

An overview of the different batches which were prepared is given in the table below:

DuroTak ® 87-4287 Eudragit ® EPO number amount [%] amount [%] I 100 0 II 90 10 III 80 20 IV 70 30 V 60 40 VI 50 50

The in vitro peel strength of Duro Tak® 87-4287 prototypes containing different amounts of Eudragit® EPO was determined. The results are summarized in the table below:

mean SD F_(max) F_(max) Eudragit ® (n = 6) (n = 6) mean SD EPO [N/ [N/ F_(mean) (n = 6) F_(mean) (n = 6) amount [%] 25 mm] 25 mm] [N/25 mm] [N/25 mm] reference 0 5.3 0.57 4.8 0.51 I 0 12.6 0.54 10.7 0.73 II 10 * * * * III 20 7.1 0.18 6.0 0.32 IV 30 5.8 0.46 4.9 0.45 V 40 5.7 0.79 4.7 0.65 VI 50 5.0 0.77 3.5 0.43 * no data obtained

A decrease of peel strength with increasing methacrylate amount could be detected. No differences in vivo between formulations III to VI could be seen (data not shown).

Example 23 Polymer Screening of Acrylates

In a series of experiments under comparable conditions, patches made of various acrylate adhesives were tested in terms of saturation solubility and stability of API free base and permeation across a synthetic EVA membrane.

The saturation concentrations of API free base in the coating masses were determined. An overview of the different batches which were prepared is given in the table below:

saturation adhesive API solubility of API batch adhesive solvent solvent free base [%] 23-1 DuroTak Ethyl acetate Toluene/2- 1.2 87-4287/ Propanol Eudragit ® EPO 23-2 DuroTak 87-2516 Ethyl acetate, Toluene/2- 0.8 Ethyl alcohol, Propanol Heptane, Methyl alcohol 23-3 DuroTak Ethyl acetate Toluene/2- 1.2 87-208A Propanol 23-4 DuroTak 87-9088 Ethyl acetate Toluene/2- 0.9 Propanol

Over a time period of four weeks at 25° C./65% r.h. and 40° C./75% r.h. there was no re-crystallization of any of patch systems 23-1 to 23-4, neither with nor without seeding crystals.

The assay under stress stability conditions at 60° C. over a period of 6 days was determined. The results are summarized in the table below:

API free base API free base assay assay after 6 days at start [n = 3] at 60° C. [n = 3] batch amount [%] SD [%] amount [%] SD [%] 23-1 104.1 1.36 103.7 1.22 23-2 100.4 0.62 97.8 1.53 23-3 98.2 0.72 97.1 0.50 23-4 93.8 1.78 94.2 0.45

The purity under stress stability conditions at 60° C. for 6 days was determined. The results are summarized in the table below:

known impurities time (n = 3) [%] unknown impurities (n = 3) [%] [days] DEGR1 DEGR2 RRT0.27 RRT0.36 RRT0.54 RRT0.60 RRT0.81 RRT0.93 23-1 0 — — 0.32 0.28 0.53 — — — 6 — 0.11 0.33 0.33 0.52 — — — 23-2 0 0.39 0.29 0.46 0.36 0.96 0.10 0.14 — 6 0.67 0.52 0.49 0.36 0.89 — 0.23 — 23-3 0 0.51 0.19 0.43 0.33 1.09 — 0.15 — 6 0.82 0.37 0.47 0.43 1.18 — 0.21 — 23-4 0 1.68 — 0.36 0.31 1.60 — — — 6 2.51 0.33 0.46 0.58 2.51 — 0.19 0.17 RRT0.27, RRT0.36, RRT0.54, RRT0.60, RRT0.81 and RRT0.93 are unknown impurities characterized by a specific HPLC retention time

FIG. 25 shows the EVA membrane permeation testing of acrylate formulations containing API free base (23-1 to 23-4) vs. an acrylate reference patch (19-13, composition 12D).

The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:

correlation steady-state steady-state coefficient flux rate adhesive interval [h] [r²] [μg/cm²/h] factor 19-13 DuroTak 87-4287 8-46 0.990 0.040 1.00 (acrylate) 23-1  DuroTak 8-54 0.991 0.076 1.90 87-4287/ Eudragit ® EPO 23-2  DuroTak 87-2516 8-46 0.993 0.045 1.13 23-3  DuroTak 8-54 0.995 0.064 1.60 87-208A 23-4  DuroTak 87-9088 8-54 0.990 0.072 1.80

It becomes evident from the above tables that a combination of DuroTak 87-4287 and Eudragit EPO lead to reduced degradation of the API free base. Furthermore, this formulation shows increased permeation increased rate in comparison to an acrylate reference patch 12D.

Example 24 Enhancer Screening

The solubility of API free base in different liquid permeation enhancer substances was determined. The results are summarized in the table below:

solubility of API enhancer free base [mg/mL] Laurocapram (Azone ®) 20.0 Levulinic acid 11.7 Diethylene glycol monoethyl ether (Transcutol P) 6.3 Benzyl alcohol 5.3 Polyethylene glycol 400 3.9 Lauryl lactate 2.6 Propylene glycol monolaurate 1.8 Dibutylene sebacate 1.5 Oleyl oleate 1.4 1-Dodecanol 1.3 Caprylic acid 1.2 Polysorbate 80 0.8 Isopropyl myristate 0.7 Glycerol 0.7 Triacetine 0.6 Isopropyl palmitate 0.5 Ethyl oleate 0.5

Out of the substances mentioned in the table above, the following enhancers were selected to be tested further.

E1 Oleyloleate E2 Isopropylmyristate E3 Levulinic acid E4 Transcutol E5 Triacetin E6 Laurocapram E7 Dodecanol E8 PEG400

The permeation of API free base across dermatomized pig skin (incl. stratum corneum) from saturated solutions in enhancers E1 to E8 has been investigated, results are shown in FIG. 15.

It becomes evident from FIG. 15 that Levulinic acid and Transcutol demonstrated both, absolute and relative, highest flux rates from saturated solutions of API free base in liquid enhancers across dermatomized pig skin.

Example 25 Eudragit® EPO Containing Polymer Systems

In a series of experiments under comparable conditions, patches made of acrylate adhesive DuroTak 87-4287 or styrenic rubber adhesive DuroTak 87-6911 in combination with Eudragit EPO were tested in terms of saturation solubility and stability of the API free base and permeation across a synthetic EVA membrane.

The saturation concentration of API free base in Eudragit® EPO containing polymer systems was determined. The results are summarized in the table below:

saturation solubility of API batch adhesive free base [%] 25-1 90% DuroTak 87-4287/10% Eudragit ® EPO 1.00 23-1 50% DuroTak 87-4287/50% Eudragit ® EPO 1.20 25-2 90% DuroTak 87-208A/10% Eudragit ® EPO 1.00 25-3 50% DuroTak 87-208A/50% Eudragit ® EPO 1.00 25-4 50% DuroTak 87-6911/50% Eudragit ® EPO 0.25 25-5 50% DuroTak 87-6911/50% Eudragit ® EPO 0.30

By adding more Eudragit® EPO to the formulation no or only a low increase of the saturation concentration of API free base in the patch could be obtained.

Over a time period of four weeks at 25° C./60% r.h. and 40° C./75% r.h. there was no re-crystallization of any of patch systems 25-1 to 25-5 and 23-4, neither with nor without seeding crystals. The patches were stored in Surlyn® pouches.

Stress stability was tested at 60° C. over a period of 6 days in Surlyn® pouches. The results are summarized in the table below:

Eudragit time API free DEGR1 DEGR2 batch adhesive [%] [days] base [%] [%] [%] 25-1 DuroTak ® 10 0 104 0.04 0.13 87-4287 6 94 0.12 0.25 23-1 50 0 104 — — 6 104 — 0.11 25-2 DuroTak ® 10 0 99 0.04 0.10 87-208A 6 92 0.12 0.23 25-3 50 0 102 — 0.08 6 95 0.04 0.21 25-4 DuroTak ® 10 0 86 — 0.17 87-6911 6 90 0.17 0.22 25-2 50 0 103 — — 6 99 — 0.10

It becomes evident from above table that by increasing the Eudragit® EPO amount in the formulation the amount of degradation products could be decreased.

FIG. 26 shows the EVA membrane permeation testing of Eudragit® EPO containing adhesives vs. an acrylate reference patch (19-13, composition 12D). In the case of DuroTak® 87-208A and DuroTak® 87-6911 an increase of the Eudragit® EPO amount decreased the thermodynamic activity. For DuroTak® 87-4287 an increase of the Eudragit® EPO content yielded an increase of the thermodynamic activity.

The EVA membrane permeation data and calculation of flux rate across the membrane is summarized in the table below:

steady-state correlation steady-state flux adhesive interval [h] coefficient [r²] rate [μg/cm²/h] factor  19-13 DuroTak 87-4287 (acrylate) 8-54 0.990 0.050 1.00 25-1 90% DuroTak 87-4287/10% 19-54  0.995 0.061 1.22 Eudragit ® EPO 23-1 50% DuroTak 87-4287/50% 19-54  0.999 0.076 1.52 Eudragit ® EPO 25-2 90% DuroTak 87-208A/10% 8-54 0.997 0.058 1.16 Eudragit ® EPO 25-3 50% DuroTak 87-208A/50% 8-54 1.000 0.039 0.78 Eudragit ® EPO 25-4 50% DuroTak 87-6911/50% 8-54 0.999 0.047 0.94 Eudragit ® EPO 25-5 50% DuroTak 87-6911/50% 8-54 0.997 0.025 0.50 Eudragit ® EPO

It becomes evident from the above tables that Eudragit EPO lead to reduced degradation of the API free base. In addition, an increased permeation rate in comparison to an acrylate reference patch 12D could be observed in combination with acrylate adhesive DuroTak 87-4287 but not in combination with the styrenic rubber adhesive DuroTak 87-6911. 

1. A pharmaceutical patch for transdermal administration of the pharmacologically active ingredient (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine or a physiologically acceptable salt thereof, the patch comprising a surface layer, an adhesive layer, and a removable protective layer, wherein the adhesive layer is located between the surface layer and the removable protective layer.
 2. The pharmaceutical patch according to claim 1, wherein the adhesive layer comprises at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.
 3. The pharmaceutical patch according to claim 2, wherein the concentration of the pharmacologically active ingredient in the adhesive layer is within the range of from 0.01 to 10 g/m² and/or within the range of from 0.01 to 10 wt.-%, relative to the total weight of the adhesive layer.
 4. The pharmaceutical patch according to claim 1, wherein the surface layer has a thickness within the range of from 0.1 to 5000 μm and/or the adhesive layer has a thickness within the range of from 1.0 to 1000 μm.
 5. The pharmaceutical patch according to claim 1, wherein the adhesive layer comprises a pressure sensitive adhesive selected from the group consisting of polysilicone based pressure sensitive adhesives, polyacrylate based pressure sensitive adhesives, polyisobutylene based pressure sensitive adhesives, and styrenic rubber based pressure sensitive adhesives.
 6. The pharmaceutical patch according to claim 1, wherein the adhesive layer comprises a copolymer comprising monomer units originating from monomers A which are selected from C₁₋₁₈-alkyl(meth)acrylates and/or monomers B which are copolymerizable with monomers A.
 7. The pharmaceutical patch according to claim 6, wherein (i) monomers A are selected from the group consisting of methyl(meth)acrylate, ethyl (meth)acrylate, propyl(meth)acrylate, butyl(meth)acrylate, pentyl(meth)acrylate, hexyl(meth)acrylate, cyclohexyl(meth)acrylate, octyl(meth)acrylate, isobornyl(meth)acrylate, and mixtures thereof; and/or (ii) monomers B are selected from the group consisting of 2-hydroxyethyl(meth)-acrylate, glyceryl mono(meth)acrylate, glycidyl(meth)acrylate, acrylamide, N,N-diethyl(meth)acrylamide, 2-ethoxyethyl(meth)acrylate, 2-ethoxyethoxyethyl(meth)acrylate, tetrahydrofuryl(meth)acrylate, vinyl acetate, N-vinyl pyrrolidone and mixtures thereof.
 8. The pharmaceutical patch according to claim 6, wherein the acrylate copolymer is derived from a monomer composition comprising vinyl acetate, 2-ethylhexyl acrylate and 2-hydroxyethyl acrylate, optionally also comprising glycidyl methacrylate.
 9. The pharmaceutical patch according to claim 1, wherein the adhesive layer comprises a permeation component which enhances permeation of the pharmacologically active ingredient through human skin.
 10. The pharmaceutical patch according to claim 9, wherein the relative weight ratio of the pharmacologically active ingredient to the permeation component is within the range of from 1:1 to 1:500.
 11. The pharmaceutical patch according to claim 9, wherein the permeation component comprises a non-cyclic compound of formula C_(2n)H_(4n+2)O_(n), where index n is 2, 3 or
 4. 12. The pharmaceutical patch according to claim 11, wherein the non-cyclic compound is diethylene glycol monomethylether, dipropylene glycol or a mixture thereof.
 13. The pharmaceutical patch according to claim 1, wherein the permeation component comprises an organic acid.
 14. The pharmaceutical patch according to claim 13, wherein the organic acid is levulinic acid.
 15. The pharmaceutical patch according to claim 1, wherein the adhesive layer comprises an antioxidant.
 16. The pharmaceutical patch according to claim 1, wherein the adhesive layer has an area within the range of from 10 to 750 cm².
 17. The pharmaceutical patch according to claim 1, which upon application to the human skin provides release of the pharmacologically active ingredient at a rate of at least 1.0 ng·cm²·h⁻¹ over a period of at least 6 hours.
 18. The pharmaceutical patch according to claim 1, which upon application to the human skin provides plasma concentrations of the pharmacologically active ingredient of at least 10 pg·ml⁻¹ over a period of at least 6 hours. 